Substituted spiro compound derivatives and their pharmaceutical use

Abstract

Provided herein are novel spiro compound derivatives, compositions containing the compounds, and preparation methods and uses thereof. The spiro compound derivatives are compounds represented by Formula (I), or tautomers, stereoisomers, prodrugs, crystal forms, isotopically labeled forms, pharmaceutically acceptable salts, hydrates or solvates thereof. The compounds and compositions of the present disclosure can be used to treat diseases or disorders mediated by USP1, in particular, cancer.

Description

SUBSTITUTED SPIRO COMPOUND DERIVATIVES AND THEIR PHARMACEUTICAL USE

[0001] The present disclosure belongs to a technical field of medicine, and particularly relates to spiro compound derivates with inhibitory effect on USP1, pharmaceutical compositions containing the same, and preparation methods and uses thereof.

[0002] Ubiquitin is a highly conserved polypeptide composed of 76 amino acids residues. It is conjugated to a substrate protein as part of a post-translational modification, which is known as a ubiquitination process. During the ubiquitination process, ubiquitin is attached to lysine residues on the substrate protein or itself, leading to monoubiqutination or polyubiquitination. Ubiquitination plays a critical role in the regulation of protein stability, function, and localization, and thus, it is involved in various cellular processes, including immune response, cell proliferation, DNA repair, etc.

[0003] Ubiquitination is a reversible process due to the presence of deubiquitination enzymes (DUBs), which can remove ubiquitin from the substrate protein. USP1 (Ubiquitin specific protease 1) is one of deubiquitination enzymes, and is known to play an important role in the regulation of DNA repair processes. In order to gain deubiquitanase activity, USP1 is associated with UAF1 (USP1-associated factor 1) to form a heterodimeric USP1 / UAF1 complex. The USP1 / UAF1 complex regulates the following two cellular pathways: Faconi anemia (FA) pathway and translesion synthesis (TLS) pathway. In the FA pathway, the USP1 / UAF1 complex deubiquitinates monoubiqutinated FANCD2 (Fanconi anemia group complentation group D2) and FANC1 (Fanconi anemia complementation group 1) proteins. In the TLS pathway, the USP1 / UAF1 complex deubiquitinates monoubiqutinated PCNA (proliferating cell nuclear antigen). The above-mentioned two pathways are known to participate in repairing DNA damage caused by DNA interstand crosslink (ICL).

[0004] Inhibition of USP1 can impair DNA damage response, mainly in the FA and TLS pathways. Based on the above-described mechanism, USP1 has been identified as a promising therapeutic target for various cancers. For example, it has been shown that USP1 inhibitors reverse cisplatin resistance in non-small cell lung cancer (NSCLC) (Chen, J., et al, 2011,Chemistry & biology,1390-1400). It has also been shown that USP1 inhibition inhibits tumor growth in osteosarcoma cells (Williams, Samuel A., et al., 2011, Cell, 146(6), 918-930; and Lim, K. H & Baek, K. H., 2013, Current pharmaceutical design, 19(22), 4039-4052), and leukemic cells (Mistry, Helena, et al., 2013, Molecular cancer therapeutics 12.12 (2013): 2651-2662).

[0005] Therefore, inhibiting USP1 has potential as a treatment for various cancers, and there is a need to develop novel small molecule compounds that have an inhibitory activity for USP1.

[0006] The present disclosure provides novel spiro compounds derivatives, compositions comprising the same, and preparation methods and uses thereof. The spiro derivatives have an inhibitory activity for USP1, and can be effectively used for treating various types of cancers.

[0007] In one aspect, the present disclosure relates to a compound of the following Formula (I):

[0008]

[0009] (I)

[0010] wherein:

[0011] A is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0012] L is selected from the group consisting of -(C2-C6alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C2-C6alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, -(C1-C6alkylene)-N(C1-C6alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0013] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto;

[0014] q is an integer between 1 to 5;

[0015] B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0016] each of W1and W2is independently selected from N and CR3, wherein each of R3is independently selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0017] each of X and Y is independently selected from the group consisting of a single bond, sulfur, oxygen, -N(R1)-, -C(O)-, and -CH(R2)-, wherein each of R1and R2is independently selected from the group consisting of hydrogen, C1-C6alkyl, hydroxy, halogen, and C1-C6alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[0018] each of n and m is independently an integer between 0 to 7, provided that when X and Y both are a single bond, m+n is greater than or equal to 2; and when either X or Y is a single bond, m+n is greater than or equal to 1,

[0019] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0020] In another aspect, the present disclosure provides a pharmaceutical composition for treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1, which comprises one or more of the compounds disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and optionally a pharmaceutically acceptable carrier(s) or excipient(s). In a specific embodiment, the composition comprises one or more of the compounds in a therapeutically effective amount. In a specific embodiment, the composition comprises one or more of the compounds in a prophylactically effective amount.

[0021] In another aspect, the present disclosure provides the use of the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein, in the manufacture of a medicament for the treatment or prevention of diseases or disorders mediated by USP1.

[0022] In another aspect, the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1, in a subject, comprising administering to the subject at least one compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein.

[0023] In another aspect, the present disclosure provides the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein, for use in treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1.

[0024] Other objects and advantages of the present disclosure will be apparent to those skilled in the art from the following specific embodiments, examples, and claims.

[0025]

[0026] Definitions

[0027] Chemical terms

[0028] The definitions of specific functional groups and chemical terms are described in more detail below.

[0029] When a range of values is listed, it is intended to encompass each value and any sub-range within the range. For example, "C1-6alkyl" is intended to encompass C1, C2, C3, C4, C5, C6, C1-6, C1-5, C1-4, C1-3, C1-2, C2-6, C2-5, C2-4, C2-3, C3-6, C3-5, C3-4, C4-6, C4-5, and C5-6alkyl.

[0030] As used herein (unless otherwise specified), the term "C1-6alkyl" refers to a saturated hydrocarbon group which is straight-chained or branched, and has 1 to 6 carbon atoms. It is also referred to herein as a "lower alkyl" group. In some embodiments, the alkyl group may have 1 to 4 carbon atoms (C1-4alkyl) or 3 to 6 carbon atoms (C3-6alkyl). Examples of C1-6alkyl group include, but are not limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, tert-butyl, sec-butyl, iso-butyl, n-pentyl, 3-pentyl, 2-pentyl, neo-pentyl, 3-methyl-2-butyl, tert-pentyl, n-hexyl, 2-hexyl, 3-hexyl, and the like.

[0031] As used herein (unless otherwise specified), the term "C1-6alkylene" refers to a divalent alkyl linking group, which is a linear or branched, saturated hydrocarbon group having 1 to 6 carbon atoms. An　alkylene　group formally corresponds to an alkane with two C-H bond replaced by points of attachment of the　alkylene　group to the remainder of the　compound. Examples of　alkylene　groups include, but are not limited to, methylene, ethylene, propan-1,3-diyl, propan-1,2-diyl, butan-l,4-diyl, butan-1,3-diyl, butan-l,2-diyl, 2-methyl-propan-1,3-diyl and the like.

[0032] As used herein (unless otherwise specified), the term "C2-6alkenyl" refers to a hydrocarbon group which is straight-chained or branched, and has 2-6 carbon atoms and one or more carbon-carbon double bonds (e.g., 1, 2, or 3 carbon-carbon double bonds). One or more carbon-carbon double bonds can be internal (e.g., in 2-butenyl) or terminal (e.g., in 1-butenyl). In some embodiments, the alkenyl group may have 2 to 4 carbon atoms. Examples of C2-6alkenyl group include, but are not limited to, vinyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, butadienyl, pentenyl, pentadienyl, hexenyl, etc.

[0033] As used herein (unless otherwise specified), the term "C2-6alkynyl" refers to a hydrocarbon group which is straight-chained or branched, and has 2-6 carbon atoms, one or more carbon-carbon triple bonds (e.g., 1, 2 or 3 carbon-carbon triple bonds) and optionally one or more carbon-carbon double bonds (e.g., 1, 2 or 3 carbon-carbon double bonds). In some embodiments, the alkynyl group may have 2 to 4 carbon atoms. In some embodiments, the alkynyl group does not contain any double bond. One or more carbon-carbon triple bonds can be internal (e.g., in 2-butynyl) or terminal (e.g., in 1-butynyl). Examples of C2-6alkynyl group include, but are not limited to, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, pentynyl, hexynyl, etc.

[0034] As used herein (unless otherwise specified), the term "C2-6alkynylene" refers to a divalent alkynyl linking group, which is a linear or branched hydrocarbon group having 2 to 6 carbon atoms and one or more carbon-carbon triple bonds. An　alkynylene　group formally corresponds to an alkyne with two C-H bonds replaced by points of attachment of the　alkynylene　group to the remainder of the　compound. Examples of　alkynylene　groups include, but are not limited to, acetylene, 1-propyn-1,3-diyl, 2-propyn-1,3-diyl, 1-butyne-1,4-diyl, 2-butyne-1,4-diyl, 3-butyne-1,4-diyl, 1-butyne-1,3-diyl, 2-butyne-1,4-diyl, 3-butyne-1,4-diyl, 3-butyne-2,4-diyl and the like.

[0035] As used herein (unless otherwise specified), the term "C1-6alkoxy" refers to a -OR group, wherein R is substituted or unsubstituted C1-6alkyl. In some embodiments, the alkoxy group may have 1 to 4 carbon atoms. Specifically, C1-6alkoxyl includes, but is not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentyloxy, n-hexyloxy and 1,2-dimethylbutoxy.

[0036] As used herein (unless otherwise specified), the terms "halo" or "halogen" refers to fluoro (F), chloro (Cl), bromo (Br) and iodo (I). In some embodiments, the halo group is F, Cl or Br. In some embodiments, the halo group is F or Cl. In some embodiments, the halo group is F.

[0037] As used herein (unless otherwise specified), the terms "carbocyclic group" refers to a non-aromatic cyclic hydrocarbon group having from 5 to 10 ring carbon and zero heteroatoms in the non-aromatic ring system. In some embodiments, the carbocyclic group may have 5 to 10, 5 to 8, 5 to 7, or 6 to 7 ring carbon atoms. As the foregoing examples illustrate, in certain embodiments, the carbocyclyl group is either monocyclic ("monocyclic carbocyclyl") or polycyclic (e.g., containing a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic carbocyclyl") or tricyclic system ("tricyclic carbocyclyl")) and can be saturated or can contain one or more carbon-carbon double or triple bonds. "Carbocyclyl" also includes ring systems wherein the carbocyclyl ring, as defined above, is fused with one or more aryl or heteroaryl groups wherein the point of attachment is on the carbocyclyl ring, and in such instances, the number of carbons continue to designate the number of carbons in the carbocyclic ring system.

[0038] As used herein (unless otherwise specified), the terms "heterocarbocyclic group" refers a group or radical of a 5- to 10-membered non-aromatic ring system having ring carbon atoms and 1 to 4 ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, and sulfur. In heterocyclyl groups that contain one or more nitrogen atoms, the point of attachment can be a carbon or nitrogen atom, as valency permits. A heterocyclic group can either be monocyclic ("monocyclic heterocyclyl") or polycyclic (e.g., a fused, bridged or spiro ring system such as a bicyclic system ("bicyclic heterocyclyl") or tricyclic system ("tricyclic heterocyclyl")), and can be saturated or can contain one or more carbon-carbon double or triple bonds. In some embodiments, the heterocarbocyclic group may have 5 to 10, 5 to 8, 5 to 7, or 6 to 7 ring atoms.

[0039] As used herein (unless otherwise specified), the terms "C3-12cyclic group" or "3-12 membered cyclic group" refers to a cyclic hydrocarbon group which is non-aromatic and has 3-12 ring carbon atoms and zero heteroatoms. In some embodiments, the cycloalkyl group may have 3 to 12, 3 to 10, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 5 to 8, 5 to 7, or 5 to 6 ring carbon atoms. The cyclic group also includes a ring system in which the above cyclic group is fused with one or more aryl or heteroaryl groups, wherein the point of attachment is on the ring of the cyclic group. Examples of the cyclic group include, but are not limited to, cyclopropyl, cyclopropenyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptenyl, cycloheptadienyl, cycloheptatrienyl, cyclooctyl, cyclooctenyl, bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, and the like.

[0040] As used herein (unless otherwise specified), the term "3-12 membered heterocyclic group", or the term "3-12 -membered heterocyclyl" refers to a radical of a 3-12 membered saturated or partially unsaturated ring system which is non-aromatic and has ring carbon atoms and at least one ring heteroatoms, wherein each heteroatom is independently selected from nitrogen, oxygen, sulfur and phosphorus. Unless stated otherwise specifically in the specification, the　heterocyclic group is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, and includes a fused, spiro, or bridged ring system. In some embodiments, the heterocyclyl group may have 2 to 7, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 5 to 12, 5 to 8, 5 to 7, 5 to 6, 9 to 11, 9 to 10 ring carbon atoms, and 1 to 4 heteroatoms. In one embodiment, the heterocyclic group may be 7-8 membered bicyclic spiro heterocyclic group.

[0041] Exemplary 3-membered heterocyclyl groups containing one heteroatom include, without limitation, azirdinyl, oxiranyl, thiorenyl. Exemplary 4-membered heterocyclyl groups containing one heteroatom include, without limitation, azetidinyl, oxetanyl and thietanyl. Exemplary 5-membered heterocyclyl groups containing one heteroatom include, without limitation, tetrahydrofuranyl, dihydrofuranyl, tetrahydrothiophenyl, dihydrothiophenyl, pyrrolidinyl, dihydropyrrolyl and pyrrolyl-2,5-dione. Exemplary 5-membered heterocyclyl groups containing two heteroatoms include, without limitation, dioxolanyl, oxasulfuranyl, disulfuranyl, and oxazolidin-2-one. Exemplary 5-membered heterocyclyl groups containing three heteroatoms include, without limitation, triazolinyl, oxadiazolinyl, and thiadiazolinyl. Exemplary 6-membered heterocyclyl groups containing one heteroatom include, without limitation, piperidinyl, tetrahydropyranyl, dihydropyridinyl, and thianyl. Exemplary 6-membered heterocyclyl groups containing two heteroatoms include, without limitation, piperazinyl, morpholinyl, pyridinonyl, dithianyl, dioxanyl. Exemplary 6-membered heterocyclyl groups containing three heteroatoms include, without limitation, pyridazinonyl triazinanyl. Exemplary 7-membered heterocyclyl groups containing one heteroatom include, without limitation, azepanyl, oxepanyl and thiepanyl. Exemplary 8-membered heterocyclyl groups containing one heteroatom include, without limitation, azocanyl, oxecanyl and thiocanyl. Exemplary 10-membered heterocyclyl groups include, without limitation, phthalazinonyl.

[0042] In one embodiment, the heterocyclic group includes a saturated ring radical that comprises carbon atoms and from heteroatoms selected from nitrogen, oxygen, sulfur and phosphorus. In an embodiment, the saturated heterocyclic group may have a 3-8 membered heterocyclic group. In an embodiment, the saturated heterocyclic group may have 8 membered bicyclic spiro heterocyclic group. In some embodiments, the saturated heterocyclic group may have 2 to 7, 3 to 8, 3 to 7, 3 to 6, 3 to 5, 3 to 4, 4 to 8, 4 to 7, 4 to 6, 5 to 8, 5 to 7, or 5 to 6 ring carbon atoms, and 1 to 4 heteroatoms. Examples of such　saturated heterocyclic group include, but are not limited to, dioxolanyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl, imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and 1,1-dioxo-thiomorpholinyl. Examples of saturated spiro heterocyclic group includes 2-oxa-7-azaspiro[3.5]nonan-7-yl.

[0043] As used herein (unless otherwise specified), the term "C6-14aryl" or "6- to 14-membered aryl" refers to a radical of a carbocyclic aromatic group, whether or not fused to one or more groups, having 6 to 14 ring carbon atoms and zero heteroatoms. In one embodiment, the aryl may have 6-10 membered ring carbon atoms. The aryl group may be monocylic or polycylic (e.g., bicyclic or tricyclic). Examples of the aryl group include, but are not limited to, phenyl, naphtyl, anthracyl, and the like. The aryl group also includes ring systems wherein the aryl ring, as defined herein, is fused with one or more cycloalkyl or heterocyclyl groups wherein the point of attachment is on the aryl ring.

[0044] As used herein (unless otherwise specified), the term "C6-14arylene" or "6- to 14-membered arylene" refers to a divalent carbocyclic aromatic group, whether or not fused to one or more groups, having 6 to 14 ring carbon atoms and zero heteroatoms. In one embodiment, the arylene may have 6-10 membered ring carbon atoms. The arylene group may be monocylic or polycylic (e.g., bicyclic or tricyclic). Examples of the arylene group include, but are not limited to, phenylene, naphtylene, anthracylene, and the like. The arylene group also includes ring systems wherein the arylene ring, as defined herein, is fused with one or more cycloalkyl or heterocyclyl groups wherein the point of attachment is on the arylene ring.

[0045] As used herein (unless otherwise specified), the term "5- to 12-membered heteroaryl" refers to any monocyclic or polycyclic (e.g., bi-, or tricyclic) aromatic ring system which has ring carbon atoms and at least one heteroatoms (e.g., nitrogen, oxygen, and sulfur). The heteroaryl group also includes ring systems wherein the heteroaryl ring, as defined herein, is fused with one or more cycloalkyl, heterocyclyl or aryl groups wherein the point of attachment is on the heteroaryl ring. In some embodiments, the heteroaryl group may have 3 to 8, 3 to 7, 4 to 7, 5 to 10, 5 to 7, or 5 to 6 ring carbon atoms or heteroatoms.

[0046] Exemplary 5-membered heteroaryl groups containing one heteroatom include, without limitation, pyrrolyl, furanyl and thiophenyl. Exemplary 5-membered heteroaryl groups containing two heteroatoms include, without limitation, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, and isothiazolyl. Exemplary 5-membered heteroaryl groups containing three heteroatoms include, without limitation, triazolyl, oxadiazolyl, and thiadiazolyl. Exemplary 5-membered heteroaryl groups containing four heteroatoms include, without limitation, tetrazolyl. Exemplary 6-membered heteroaryl groups containing one heteroatom include, without limitation, pyridinyl. Exemplary 6-membered heteroaryl groups containing two heteroatoms include, without limitation, pyridazinyl, pyrimidinyl, and pyrazinyl. Exemplary 6-membered heteroaryl groups containing three or four heteroatoms include, without limitation, triazinyl (e.g., 1,2,4-triazinyl, 1,3,5-triazinyl), and tetrazinyl, respectively. Exemplary 7-membered heteroaryl groups containing one heteroatom include, without limitation, azepinyl, oxepinyl, and thiepinyl. Exemplary 5,6-bicyclic heteroaryl groups include, without limitation, indolyl, isoindolyl, indazolyl, benzotriazolyl, benzothiophenyl, isobenzothiophenyl, benzofuranyl, benzoisofuranyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzoxadiazolyl, benzthiazolyl, benzisothiazolyl, benzthiadiazolyl, indolizinyl, and purinyl. Exemplary 6,6-bicyclic heteroaryl groups include, without limitation, naphthyridinyl, pteridinyl, quinolinyl, isoquinolinyl, cinnolinyl, quinoxalinyl, phthalazinyl, and quinazolinyl.

[0047] As used herein (unless otherwise specified), the term "carbamoyl" refers to the group -C(=O)- NR'R", where R' and R" independently represent a hydrogen or C1-6alkyl group.

[0048] As used herein (unless otherwise specified), the term "7-11 membered polycylic cycloalkylene" refers to a divalent cycloalkyl linking group, which is a polycyclic (where there are two or more rings) (e.g., bicyclic) hydrocarbon ring system having 7-11 ring carbon. A polycyclic ring system may be a fused ring ring system, a bridged ring system and a spiro ring system. Which system depends on the bridgehead carbon, which is defined as a carbon atom which is shared by at least two rings. A fused ring ring system is a system in which the two or more rings share a covalent bond and have two　bridgehead　carbons. A bridged ring system is a system in which there is a carbon that is part of two or more rings and the two or more rings are connected by a bridge containing two bridegehead carbons and there are one or more carbons between the two bridegehead carbons. A spiro ring system is a system in which the two or more rings are joined with a single bridgehead carbon. Examples of polycyclic cycloalkylene are cubanylene, bicyclo[2.2.1]heptylene (C7), bicyclo[2.2.2]octylene (C8) and the like.

[0049] As used herein, the terms "optional" or "optionally" mean that the subsequently described event or circumstance may occur or may not occur, and that the description includes instances where the event or circumstance occurs as well as instances in which it does not. For example, "optionally substituted" refers to the event or circumstance that a chemical group (for example, the groups defined herein) may be substituted as well as the event or circumstance where a chemical group　is not substituted.

[0050] The term "substituted" refers to moieties having　substituents　replacing hydrogen on one or more carbons of the backbone. It will be understood that "substitution" or "substituted with" includes the implicit proviso that such substitution is in accordance with permitted valence of the substituted atom and the substituent, and that the substitution results in a stable　compound, e.g., which does not spontaneously undergo transformation such as by rearrangement, cyclization, elimination, etc. As used herein, the term "substituted" is contemplated to include all permissible　substituents　of organic　compounds. Exemplary substituents on carbon atoms include, but are not limited to, C1-6alkyl, halogen, cyano, deuterium, C2-6alkenyl, C1-6alkoxy, -(C1-6alkylene)-OH, -(C1-6alkylene)-O-(C1-6alkyl), 3-10 membered (e.g., 3-8 membered, 5-6 membered, 3-5 membered) cycloalkyl, hydroxy, amino, -NH2, -NH(C1-6alkyl), -N(C1-6alkyl)(C1-6alkyl), -(C1-C6alkylene)-N(C1-C6alkyl)2, mercapto, -S(C1-6alkyl), -SO2(C1-6alkyl), carbamoyl, oxo, a 3-8 (e.g, 3-6) membered heterocyclic or heteroaryl group, -CORz1(wherein Rz1is selected from the group consisting of hydrogen, C1-6alkyl, 3-8 membered cycloalkyl, and halogen), and and -CON(Rz2)(Rz3) (wherein each of Rz2and Rz3is independently selected from the group consisting of hydrogen, C1-6alkyl, or halogen, wherein said alkyl is optionally substituted with one or more selected from C1-6alkyl and halogen; or Rz2and Rz3, taken together with the nitrogen atom to which they are attached, form a nitrogen-containing 3- to 8-membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C1-6alkyl and halogen), wherein each of said alkyl, alkenyl, alkoxy, alkylene, cycloalkyl, heterocyclic or heteroaryl is independently optionally substituted with one or more selected from C1-6alkyl and halogen. The number of substituents may be any number as long as valence of ths substitued atom and the substituent permit, for example 1 to 5, 1 to 4, 1 to 3, 1 to 2, 2 to 5, 2 to 4, 2 to 3, 3 to 5, 3 to 4, and the like.

[0051]

[0052] General terms

[0053] The term "about", when used with a corresponding numeric value, is meant to encompass variations within ± 20% of the numeric value, typically ± 10% of the numeric value, often ± 5% of the numeric value, and most often ± 2% of the numeric value. In some embodiments, the term "about" can mean the numeric value itself.

[0054] Unless particularly stated otherwise, the concept of any expression in singular form should be considered to encompass the concept of the expression in plural form. Therefore, unless particularly stated otherwise, the concept of any article that expresses the concept of singular (for example, "a", "an", "the", and the like in the case of English language) should be considered to encompass the concept of plural.

[0055] Unless particularly stated otherwise, any term used in the present description should be considered as having the conventional meaning for the relevant technical field. Therefore, unless defined otherwise, all the scientific terms and other technical terms used in the present description have the meaning that is generally understood by those skilled in the art to which the present invention pertains. If there is any conflict in meaning, the present description (including the definitions) takes priority.

[0056] Compounds

[0057] According to an aspect of the present disclosure, provided is a compound of Formula (I), (including subsets of each formula), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0058] As used herein, "compound of the present disclosure" refers to the following compound of Formula (I) (including subsets of each formula), or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0059] In one embodiment, the present disclosure relates to a compound of Formula (I):

[0060]

[0061] (I)

[0062] wherein:

[0063] A is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0064] L is selected from the group consisting of -(C2-C6alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C2-C6alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, -(C1-C6alkylene)-N(C1-C6alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0065] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto;

[0066] q is an integer between 1 to 5;

[0067] B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0068] each of W1and W2is independently selected from N and CR3, wherein each of R3is independently selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0069] each of X and Y is independently selected from the group consisting of a single bond, sulfur, oxygen, -N(R1)-, -C(O)-, and -CH(R2)-, wherein each of R1and R2is independently selected from the group consisting of hydrogen, C1-C6alkyl, hydroxy, halogen, and C1-C6alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[0070] each of n and m is independently an integer between 0 to 7, provided that when X and Y both are a single bond, m+n is greater than or equal to 2; and when either X or Y is a single bond, m+n is greater than or equal to 1,

[0071] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[0072]

[0073] Ring A, and L

[0074] In one embodiment,

[0075] A is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0076] L is selected from the group consisting of -(C2-C6alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C2-C6alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, -(C1-C6alkylene)-N(C1-C6alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0077] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto; and

[0078] X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0079]

[0080] In one embodiment, A is selected from the group consisting of 5-8 membered monocyclic heteroaryl, 8-12 membered bicyclic heteroaryl, 5-8 membered monocyclic heterocyclyl, and 8-12 membered bicyclic heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and L, X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0081] In one embodiment, A is selected from the group consisting of 5-6 membered monocyclic heteroaryl, 9-11 membered fused bicyclic heteroaryl, 5-6 membered monocyclic heterocyclyl, and 9-11 membered fused bicyclic heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and L, X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0082]

[0083] In one embodiment, A is selected from the group consisting of 5-6 membered monocyclic heteroaryl, 5-6 membered monocyclic heterocyclyl, and 9-10 membered fused bicyclic heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, oxo, and 3-5 membered heterocyclyl, wherein each of said alkyl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and L, X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0084] In one embodiment, A is selected from the group consisting of:

[0085]

[0086]

[0087]

[0088]

[0089]

[0090] wherein:

[0091] each of Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, and Ra7is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0092] preferably,

[0093] each of Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, and Ra7is independently selected from the group consisting of hydrogen, C1-C6alkyl, halogen, and 3-6 membered heterocyclyl, wherein each of said alkyl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[0094] more preferably,

[0095] each of Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, and Ra7is independently selected from the group consisting of hydrogen, C1-C6alkyl, and 3-5 membered heterocyclyl, wherein each of said alkyl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[0096] still more preferably,

[0097] each of Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, and Ra7is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl,

[0098]

[0099] (wherein Raais selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromom, and iodo); and

[0100] L, X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0101] In one embodiment, A is

[0102]

[0103] wherein each of Ra1, Ra2, and Ra3is independently selected from the group consisting of hydrogen, isopropyl, trifluoromethyl, and and

[0104] L, X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0105] In one embodiment, Ra1is isopropyl or

[0106] Ra2is trifluoromethyl;

[0107] Ra3is hydrogen; and

[0108] L, X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0109] In one embodiment, A is

[0110]

[0111] wherein each of Ra2, Ra3, and Ra4is independently selected from the group consisting of hydrogen, methyl, and trifluoromethyl; and

[0112] L, X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0113] In one embodiment, Ra2is trifluoromethyl; Ra3is hydrogen; Ra4is methyl; and L, X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0114] In one embodiment, A is

[0115]

[0116] wherein each of Ra1, Ra2, and Ra3is hydrogen; and

[0117] L, X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0118] In one embodiment, A is

[0119]

[0120] wherein each of Ra1, Ra2, Ra3, Ra4, and Ra5is hydrogen; and

[0121] L, X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0122]

[0123] In one embodiment, L is selected from the group consisting of -(C2-C6alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C2-C6alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, and -(C1-C6alkylene)-N(C1-C6alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and ring A, X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0124] In one embodiment, L is selected from the group consisting of -(6-14 membered arylene)-, -(7-9 membered polycyclic cycloalkylene)-, -(6-14 membered arylene)-NH-, and -(7-9 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, C1-C6alkoxy, amino, mercapto, and -(C1-C6alkylene)-N(C1-C6alkyl)2, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and ring A, X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0125] In one embodiment, L is selected from the group consisting of -(6-14 membered arylene)-, and -(7-9 membered bridged, fused, or sprio polycyclic cycloalkylene)-, wherein said arylene is optionally substituted with one or more selected from C1-C6alkyl, C1-C6alkoxy, and -(C1-C6alkylene)-N(C1-C6alkyl)2, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and ring A, X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0126] In one embodiment, L is selected from the group consisting of -phenylene-, and -(7-9 membered bridged polycyclic cycloalkylene)-, wherein said phenylene is optionally substituted with one or more selected from C1-C6alkyl, C1-C6alkoxy, and -(C1-C6alkylene)-N(C1-C6alkyl)2, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and ring A, X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0127]

[0128] In one embodiment, L is selected from the group consisting of -phenylene-,

[0129] wherein said phenylene is optionally substituted with one or more selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -CH2N(CH3)2, -CH2N(CH2CH3)2, and -CH2N(CH(CH3)2)2; and ring A, X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0130]

[0131] In one embodiment, L is selected from the group consisting of -phenylene-, and

[0132] wherein said phenylene is optionally substituted with one or more selected from methyl, methoxy, difluoromethoxy, and -CH2N(CH3)2; and ring A, X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0133]

[0134] In one embodiment, L is selected from the group consisting of:

[0135]

[0136] ring A, X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0137]

[0138] In one embodiment,

[0139] A is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is substituted with RL1;

[0140] L is -(6-14 membered arylene)-, wherein said arylene is substituted with RL2;

[0141] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto; and

[0142] X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0143]

[0144] In one embodiment,

[0145] A is 5-12 membered heteroaryl, wherein each of said heteroaryl is substituted with RL1;

[0146] L is phenylene, wherein said phenylene is substituted with RL2;

[0147] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto; and

[0148] X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0149]

[0150] In one embodiment,

[0151] A is 5-12 membered heteroaryl, wherein each of said heteroaryl is substituted with RL1;

[0152] L is phenylene, wherein said phenylene is substituted with RL2;

[0153] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 6-9 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, and mercapto; and

[0154] X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0155]

[0156] In one embodiment,

[0157] A is selected from the group consisting of

[0158]

[0159] each of Ra2and Ra3is independently selected from the group consisting of hydrogen, methyl, isopropyl, trifluoromethyl, and

[0160] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 6-9 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, and mercapto; and

[0161] X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0162]

[0163] In one embodiment,

[0164] wherein each of Ra2and Ra3is independently selected from the group consisting of hydrogen, methyl, isopropyl, trifluoromethyl, and

[0165] each of RL11, RL12, and RL13is selected the group consisting of hydrogen, C1-C6alkyl, and halogen, preferably, each of RL11, RL12, and RL13is selected the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromo, and iodo; and

[0166] X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0167]

[0168] In one embodiment,

[0169] X, Y, Z, W1, W2, ring B, n, m, p, and q are as defined above.

[0170]

[0171] q

[0172] In one embodiment, an integer between 1 to 5; and ring A, L, X, Y, Z, W1, W2, ring B, n, m, and p are as defined above. In one embodiment, q is 1, 2, 3, or 4; and ring A, L, X, Y, Z, W1, W2, ring B, n, m, and p are as defined above. In one embodiment, q is 1, 2, or 3; and ring A, L, X, Y, Z, W1, W2, ring B, n, m, and p are as defined above. In one embodiment, q is 1; and ring A, L, X, Y, Z, W1, W2, ring B, n, m, and p are as defined above.

[0173]

[0174] Ring B

[0175] In one embodiment, B is 5-12 membered heteroaryl, preferably, 5-10 membered heteroaryl, more preferably, 5-6 membered heteroaryl, still more preferably, 5-6 membered heteroaryl, including 1-4 heteroatoms selected from N, O and S, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and L, X, Y, Z, W1, W2, ring A, n, m, p, and q are as defined above.

[0176] In one embodiment, B is selected from the group consisting of imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazoly, furanyl, thiophenyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and traizinyl, which is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and L, X, Y, Z, W1, W2, ring A, n, m, p, and q are as defined above.

[0177] In one embodiment, B is selected from the group consisting of pyridinyl, pyridzainyl, pyrimidinyl, and pyrazinyl, which is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl, and L, X, Y, Z, W1, W2, ring A, n, m, p, and q are as defined above.

[0178] In one embodiment, B is 5-12 membered heteroaryl, preferably, 5-10 membered heteroaryl, more preferably, 5-6 membered heteroaryl, still more preferably, 5-6 membered heteroaryl, including 1-4 heteroatoms selected from N, O and S, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, 3-10 membered cycloalkyl, halogen, cyano, hydroxy, and C1-C6alkoxy, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and hydroxy; preferably, said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, 3-10 membered cycloalkyl, and C1-C6alkoxy, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and L, X, Y, Z, W1, W2, ring A, n, m, p, and q are as defined above.

[0179] In one embodiment, B is selected from the group consisting of imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazoly, furanyl, thiophenyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and traizinyl, which is optionally substituted with one or more selected from C1-C6alkyl, 3-10 membered cycloalkyl, halogen, cyano, hydroxy, and C1-C6alkoxy, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and hydroxy; and L, X, Y, Z, W1, W2, ring A, n, m, p, and q are as defined above.

[0180] In one embodiment, B is selected from the group consisting of imidazolyl, pyrrolyl, pyrazolyl, triazolyl, tetrazoly, furanyl, thiophenyl, oxazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, and traizinyl, which is optionally substituted with C1-C6alkyl, 3-10 membered cycloalkyl, and C1-C6alkoxy, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and L, X, Y, Z, W1, W2, ring A, n, m, p, and q are as defined above.

[0181] In one embodiment, B is selected from the group consisting of pyridinyl, pyridzainyl, pyrimidinyl, and pyrazinyl, which is optionally substituted with one or more selected from C1-C6alkyl, 3-10 membered cycloalkyl, halogen, cyano, hydroxy, and C1-C6alkoxy, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, and hydroxy; and L, X, Y, Z, W1, W2, ring A, n, m, p, and q are as defined above.

[0182] In one embodiment, B is selected from the group consisting of pyridinyl, pyridzainyl, pyrimidinyl, and pyrazinyl, which is optionally substituted with one or more selected from C1-C6alkyl, 3-10 membered cycloalkyl, and C1-C6alkoxy, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen; and L, X, Y, Z, W1, W2, ring A, n, m, p, and q are as defined above.

[0183]

[0184] In one embodiment, B is selected from the group consisting of:

[0185]

[0186] wherein:

[0187] each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, or carbamoyl,

[0188] preferably, each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, 3-10 membered cycloalkyl, and C1-C6alkoxy, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[0189] more preferably, each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy; and

[0190] L, X, Y, Z, W1, W2, ring A, n, m, p, and q are as defined above.

[0191]

[0192] In one embodiment, B is

[0193]

[0194] wherein:

[0195] each of Rb1, Rb2, and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, or carbamoyl,

[0196] preferably, each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, 3-10 membered cycloalkyl, and C1-C6alkoxy, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[0197] more preferably, each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy; and

[0198] L, X, Y, Z, W1, W2, ring A, n, m, p, and q are as defined above.

[0199]

[0200] In one embodiment, Rb1is methoxy; Rb2is hydrogen; Rb3is cyclopropyl; and L, X, Y, Z, W1, W2, ring A, n, m, p, and q are as defined above.

[0201]

[0202] In one embodiment, B is

[0203]

[0204] wherein:

[0205] each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, or carbamoyl,

[0206] preferably, each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, C1-C6alkyl, 3-10 membered cycloalkyl, and C1-C6alkoxy, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[0207] more preferably, each of Rb1, Rb2, Rb3, and Rb4is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy; and

[0208] L, X, Y, Z, W1, W2, ring A, n, m, p, and q are as defined above.

[0209]

[0210] In one embodiment, Rb1, Rb2, and Rb3is hydrogen; Rb4is isopropyl; and L, X, Y, Z, W1, W2, ring A, n, m, p, and q are as defined above.

[0211]

[0212]

[0213] In one embodiment, each of W1and W2is independently selected from N and CR3, wherein each of R3is independently selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and L, X, Y, Z, ring A, ring B, n, m, p, and q are as defined above.

[0214] In one embodiment, each of W1and W2is independently selected from N and CR3, wherein each of R3is independently selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, amino, and mercapto, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and L, X, Y, Z, ring A, ring B, n, m, p, and q are as defined above.

[0215] In one embodiment, each of W1and W2is independently selected from N and CR3, wherein each of R3is independently selected from hydrogen, C1-C6alkyl, and halogen, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, and halogen; and L, X, Y, Z, ring A, ring B, n, m, p, and q are as defined above.

[0216] In one embodiment, each of W1and W2is independently selected from N and CR3, wherein each of R3is independently selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, fluoro, chloro, bromo, iodo, and trifluoromethyl; and L, X, Y, Z, ring A, ring B, n, m, p, and q are as defined above.

[0217] In one embodiment, W1is selected from N and CR3, wherein R3is independently selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, fluoro, chloro, bromo, iodo, and trifluoromethyl; W2is selected from N and CR3, wherein R3is independently selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, fluoro, chloro, bromo, iodo, and trifluoromethyl; and L, X, Y, Z, ring A, ring B, n, m, p, and q are as defined above.

[0218] In one embodiment, W1is selected from N, CH, and CF; W2is selected from N and CH; and L, X, Y, Z, ring A, ring B, n, m, p, and q are as defined above.

[0219] In one embodiment, W1is selected from N and CF; W2is CH; and L, X, Y, Z, ring A, ring B, n, m, p, and q are as defined above.

[0220]

[0221] X, Y, n, and m

[0222] In one embodiment, each of X and Y is independently selected from the group consisting of a single bond, sulfur, oxygen, -N(R1)-, -C(O)-, and -CH(R2)-, wherein each of R1and R2is independently selected from the group consisting of hydrogen, C1-C6alkyl, hydroxy, halogen, and C1-C6alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and each of n and m is independently an integer between 0 to 7, provided that when X and Y both are a single bond, m+n is greater than or equal to 2; and when either X or Y is a single bond, m+n is greater than or equal to 1; andL, Z, W1, W2, ring A, ring B, p, and q are as defined above.

[0223] In one embodiment, each of X and Y is a single bond; m is 0; n is an integer between 2 to 7; and L, Z, W1, W2, ring A, ring B, p, and q are as defined above.

[0224]

[0225] In one embodiment, the ring moiety of the spiro structure of the compound of Formula is selected from the group consisting of:

[0226] ; and L, Z, W1, W2, ring A, ring B, p, and q are as defined above.

[0227]

[0228] In one embodiment, the ring moiety of the spiro structure of the compound of Formula is selected from the group consisting of:

[0229] ; and L, Z, W1, W2, ring A, ring B, p, and q are as defined above.

[0230]

[0231] Non-limiting exemplary embodiments

[0232]

[0233] In one embodiment, the present disclosure relates to a compound of Formula (Ia):

[0234]

[0235] (Ia)

[0236] wherein:

[0237] A is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0238] L is selected from the group consisting of -(C2-C6alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C2-C6alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, -(C1-C6alkylene)-N(C1-C6alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0239] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto;

[0240] q is an integer between 1 to 5;

[0241] B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0242] each of W1and W2is independently selected from N and CR3, wherein each of R3is independently selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[0243] n is an integer between 2 to 7,

[0244] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0245]

[0246] In one embodiment, the present disclosure relates to a compound of Formula (Ib):

[0247]

[0248] (Ib)

[0249] wherein:

[0250] A is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0251] L is selected from the group consisting of -(C2-C6alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C2-C6alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, -(C1-C6alkylene)-N(C1-C6alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0252] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto;

[0253] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0254] W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0255] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[0256] n is an integer between 2 to 7,

[0257] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0258]

[0259] In one embodiment,

[0260] A is selected from the group consisting of 5-6 membered monocyclic heteroaryl, 5-6 membered monocyclic heterocyclyl, and 9-10 membered fused bicyclic heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, oxo, 3-5 membered heterocyclyl, and RL1, wherein each of said alkyl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[0261] L is selected from the group consisting of -phenylene-, and -(7-9 membered bridged polycyclic cycloalkylene)-, wherein said phenylene is optionally substituted with one or more selected from C1-C6alkyl, C1-C6alkoxy, -(C1-C6alkylene)-N(C1-C6alkyl)2, and RL2, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[0262] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 6-9 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, and mercapto;

[0263] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, 3-10 membered cycloalkyl, halogen, and C1-C6alkoxy, wherein each of said alkyl, cycloalkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[0264] W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, amino, and mercapto, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[0265] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, halogen, cyano, hydroxy, amino, and mercapto, wherein said alkyl is optionally substituted with one or more selected from C1-C6alkyl, and halogen; and

[0266] n is an integer between 2 to 5.

[0267]

[0268] In one embodiment,

[0269] A is selected from the group consisting of:

[0270]

[0271]

[0272]

[0273]

[0274] each of Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, and Ra7is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, RL1,

[0275]

[0276] (wherein Raais selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromom, and iodo);

[0277] L is selected from the group consisting of -phenylene-, , , and , wherein said phenylene is optionally substituted with one or more selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -CH2N(CH3)2, -CH2N(CH2CH3)2, -CH2N(CH(CH3)2)2, and RL2;

[0278] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 6-9 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, and mercapto;

[0279] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy;

[0280] W1is selected from N and CR3, wherein R3is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, fluoro, chloro, bromo, iodo, and trifluoromethyl;

[0281] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy; and

[0282] n is an integer between 2 to 5.

[0283]

[0284] In one embodiment, the present disclosure relates to a compound of Formula (Ic-1), Formula (Ic-2), Formula (Ic-3), or Formula (Ic-4):

[0285]

[0286] (Ic-1)

[0287]

[0288] (Ic-2)

[0289]

[0290] (Ic-3)

[0291]

[0292] (Ic-4)

[0293] wherein:

[0294] each of Ra1, Ra2, Ra3, Ra4, and Ra5is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0295] preferably,

[0296] each of Ra1, Ra2, Ra3, Ra4, and Ra5is independently selected from the group consisting of hydrogen, C1-C6alkyl, oxo, and 3-5 membered heterocyclyl, wherein each of said alkyl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[0297] more preferably,

[0298] each of Ra1, Ra2, Ra3, Ra4, and Ra5is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl,

[0299] ,

[0300] (wherein Raais selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromom, and iodo);

[0301] each of RL21, RL22, RL23, and RL24is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, and -(C1-C6alkylene)-N(C1-C6alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0302] preferably,

[0303] each of RL21, RL22, RL23, and RL24is independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, and -(C1-C6alkylene)-N(C1-C6alkyl)2, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[0304] more preferably,

[0305] each of RL21, RL22, RL23, and RL24is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -CH2N(CH3)2, -CH2N(CH2CH3)2, and -CH2N(CH(CH3)2)2;

[0306] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0307] preferably,

[0308] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy;

[0309] W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0310] preferably,

[0311] W1is selected from N and CR3, wherein R3is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, fluoro, chloro, bromo, iodo, and trifluoromethyl;

[0312] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0313] preferably,

[0314] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy; and

[0315] n is an integer between 2 to 7, preferably, an integer between 2 to 5,

[0316] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0317]

[0318] In one embodiment, the present disclosure relates to a compound of Formula (Ic-1):

[0319]

[0320] (Ic-1)

[0321] wherein:

[0322] Ra1is isopropyl or ;

[0323] Ra2is trifluoromethyl;

[0324] Ra3is hydrogen;

[0325] RL21is hydrogen, or methyl;

[0326] RL22is hydrogen, or methoxy;

[0327] RL23is hydrogen;

[0328] RL24is selected from the group consisting of hydrogen, methoxy, difluoromethoxy, methyl, -CH2N(CH3)2;

[0329] Rb1is methoxy or CH;

[0330] Rb3is cyclopropyl, or iso-propyl;

[0331] W1is N or CF3;

[0332] W3is N or CH; and

[0333] n is an integer between 2 to 5,

[0334] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0335]

[0336] In one embodiment, the present disclosure relates to a compound of Formula (Ic-2):

[0337]

[0338] (Ic-2)

[0339] wherein:

[0340] Ra2is trifluoromethyl;

[0341] Ra3is hydrogen;

[0342] Ra4is methyl;

[0343] RL21is hydrogen;

[0344] RL22is hydrogen;

[0345] RL23is hydrogen;

[0346] RL24is hydrogen;

[0347] Rb1is methoxy;

[0348] Rb3is cyclopropyl;

[0349] W1is N;

[0350] W3is N; and

[0351] n is 2,

[0352] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0353]

[0354] In one embodiment, the present disclosure relates to a compound of Formula (Ic-3):

[0355]

[0356] (Ic-3)

[0357] wherein:

[0358] each of Ra1, Ra2, and Ra3is hydrogen;

[0359] each of RL21, RL22, RL23, and RL24is hydrogen;

[0360] Rb1is methoxy;

[0361] Rb3is cyclopropyl;

[0362] W1is N;

[0363] W3is N; and

[0364] n is 2,

[0365] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0366]

[0367] In one embodiment, the present disclosure relates to a compound of Formula (Ic-4):

[0368]

[0369] (Ic-4)

[0370] wherein:

[0371] each of Ra1, Ra2, Ra3, Ra4, and Ra5is hydrogen;

[0372] each of RL21, RL22, RL23, and RL24is hydrogen;

[0373] Rb1is methoxy;

[0374] Rb3is cyclopropyl;

[0375] W1is N;

[0376] W3is N; and

[0377] n is 2,

[0378] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0379]

[0380] In one embodiment, the present disclosure relates to a compound of Formula (Ic-5):

[0381]

[0382] (Ic-5)

[0383] wherein:

[0384] each of Ra2and Ra3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0385] preferably,

[0386] each of Ra2and Ra3is independently selected from the group consisting of hydrogen, C1-C6alkyl, oxo, 3-5 membered heterocyclyl, and RL1, wherein each of said alkyl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[0387] more preferably,

[0388] each of Ra2and Ra3is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, RL1,

[0389] ,

[0390] (wherein Raais selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromom, and iodo),

[0391] still more preferably,

[0392] Ra2is trifluoromethyl, and Ra3is hydrogen;

[0393] each of RL11, RL12, and RL13is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto,

[0394] preferably,

[0395] each of RL11, RL12, and RL13is selected from the group consisting of hydrogen, C1-C6alkyl, and halogen,

[0396] more preferably,

[0397] each of RL11, RL12, and RL13is selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromo, and iodo,

[0398] still more preferably,

[0399] RL11is methyl or hydrogen, RL12is hydrogen, and RL13is hydrogen;

[0400] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0401] preferably,

[0402] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy,

[0403] more preferably,

[0404] Rb1is methoxy, and Rb3is cyclopropyl;

[0405] W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0406] preferably,

[0407] W1is selected from N and CR3, wherein R3is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, fluoro, chloro, bromo, iodo, and trifluoromethyl,

[0408] more preferably,

[0409] W1is N;

[0410] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0411] preferably,

[0412] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy,

[0413] more preferably,

[0414] W3is N; and

[0415] n is an integer between 2 to 7, preferably, an integer between 2 to 5, more preferably 2,

[0416] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0417]

[0418] In one embodiment, the present disclosure relates to a compound of Formula (Ic-6):

[0419]

[0420] (Ic-6)

[0421] wherein:

[0422] each of Ra1, Ra2, and Ra3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0423] preferably,

[0424] each of Ra1, Ra2, and Ra3is independently selected from the group consisting of hydrogen, C1-C6alkyl, oxo, 3-5 membered heterocyclyl, and RL1, wherein each of said alkyl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[0425] more preferably,

[0426] each of Ra1, Ra2, and Ra3is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, RL1,

[0427] ,

[0428] (wherein Raais selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromom, and iodo),

[0429] still more preferably,

[0430] Ra1is isopropyl, Ra2is trifluoromethyl, and Ra3is hydrogen;

[0431] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0432] preferably,

[0433] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy,

[0434] more preferably,

[0435] Rb1is methoxy, and Rb3is cyclopropyl;

[0436] W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0437] preferably,

[0438] W1is selected from N and CR3, wherein R3is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, fluoro, chloro, bromo, iodo, and trifluoromethyl,

[0439] more preferably,

[0440] W1is N;

[0441] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl,

[0442] preferably,

[0443] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy,

[0444] more preferably,

[0445] W3is N; and

[0446] n is an integer between 2 to 7, preferably, an integer between 2 to 5, more preferably 2,

[0447] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0448]

[0449] In one embodiment, the present disclosure relates to a compound of Formula (Id), or (Ig):

[0450]

[0451] (Id)

[0452]

[0453] (Ig)

[0454] wherein:

[0455] A is 5-12 membered heteroaryl, wherein said heteroaryl is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0456] L is selected from the group consisting of -(C2-C6alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C2-C6alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, -(C1-C6alkylene)-N(C1-C6alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0457] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto;

[0458] q is an integer between 1 to 5;

[0459] B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0460] W2is selected from N and CR3, wherein each of R3is independently selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0461] n is an integer between 2 to 7;

[0462] Halwis halogen; and

[0463] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0464]

[0465] In one embodiment,

[0466] A is selected from the group consisting of:

[0467]

[0468]

[0469] each of Ra1, Ra2, Ra3, Ra4, and Ra5is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, RL1,

[0470] ,

[0471] (wherein Raais selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromom, and iodo);

[0472] L is selected from the group consisting of -phenylene-, , , and , wherein said phenylene is optionally substituted with one or more selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -CH2N(CH3)2, -CH2N(CH2CH3)2, -CH2N(CH(CH3)2)2, and RL2;

[0473] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 6-9 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, and mercapto;

[0474] q is 1;

[0475] B is pyridinyl or pyrimidinyl, which is optionally substituted with one or more selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy;

[0476] W2is CH;

[0477] n is an integer between 2 to 5; and

[0478] Halwis fluoro.

[0479]

[0480] In one embodiment, the present disclosure relates to a compound of Formula (Ie), or (If):

[0481] (Ie)

[0482]

[0483] (If)

[0484] wherein:

[0485] L is selected from the group consisting of -(C2-C6alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C2-C6alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, -(C1-C6alkylene)-N(C1-C6alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0486] B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[0487] each of W1and W2is independently selected from N and CR3, wherein each of R3is independently selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[0488] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof.

[0489]

[0490] In one embodiment,

[0491] L is selected from the group consisting of -phenylene-, , , and , wherein said phenylene is optionally substituted with one or more selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -CH2N(CH3)2, -CH2N(CH2CH3)2, -CH2N(CH(CH3)2)2, and RL2;

[0492] B is pyridinyl or pyrimidinyl, which is optionally substituted with one or more selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy;

[0493] W2is CH; and

[0494] W1is selected from N and CR3, wherein R3is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, fluoro, chloro, bromo, iodo, and trifluoromethyl.

[0495]

[0496] In one embodiment, the exemplary compounds of Formula (I) are provided below:

[0497]

[0498] NO.StructureNO.Structure1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

[0499]

[0500]

[0501] As used herein, the term "tautomer" or "tautomeric form" refers to structural isomers of different energies which are interconvertible via a low energy barrier. For example, proton tautomers (also known as prototropic tautomers) include interconversions via migration of a proton, such as keto-enol and imine-enamine isomerizations. Valence tautomers include interconversions by reorganization of some of the bonding electrons.

[0502] As used herein, the term "stereoisomers" refers to　compounds that have identical chemical constitution, but differ with regard to the arrangement of the atoms or groups in space. Stereoisomers include diastereomers, enantiomers, conformers and the like.

[0503] As used herein, the term "diastereomer" refers to a stereoisomer with two or more centers of chirality and whose molecules are not mirror images of one another. Diastereomers have different physical properties, e.g., melting points, boiling points, spectral properties or biological activities. Mixtures of diastereomers may be separated into each stereoisomer under high resolution analytical procedures such as electrophoresis and chromatography such as HPLC.

[0504] As used herein, the term "enantiomers" refers to two stereoisomers of a　compound　which are non-superimposable mirror images of one another.

[0505] The terms "racemic mixture" and "racemate" refer to an equimolar mixture of two enantiomeric species, devoid of optical activity.

[0506] It will be understood by those skilled in the art that the organic compounds can form complexes with solvents in which they are reacted or from which they are precipitated or crystallized. These complexes are known as "solvates." Where the solvent is water, the complex is known as "hydrate." The present disclosure encompasses all solvates of the compounds disclosed herein. Conventional solvents include water, methanol, ethanol, acetic acid, DMSO, THF, diethyl ether, etc. The compounds described herein can be prepared, for example, in crystalline form, and can be solvated. Suitable solvates include pharmaceutically acceptable solvates and further include both stoichiometric solvates and non-stoichiometric solvates. In some cases, the solvates will be capable of isolation, for example, when one or more solvent molecules are incorporated into the crystal lattice of a crystalline solid. "Solvate" means both solution-phase and isolatable solvates. Representative solvates include hydrates, ethanolates and methanolates.

[0507] The term "hydrate" refers to a compound that is associated with water. Generally, the number of water molecules contained in a hydrate of a compound is in a definite ratio to the number of the compound molecules in the hydrate. Therefore, hydrates of a compound can be represented, for example, by a general formula R x H2O, wherein R denotes the compound, and x is a number greater than 0. Given compounds can form more than one type of hydrate, including, for example, monohydrates (x is 1), lower hydrates (x is a number greater than 0 and smaller than 1, for example, hemihydrates (R 0.5 H2O)) and polyhydrates (x is a number greater than 1, for example, dihydrates (R 2 H2O) and hexahydrates (R 6 H2O)).

[0508] Compounds disclosed herein may be in an amorphous or crystalline form (crystal form or polymorph). Furthermore, the compounds disclosed herein may exist in one or more crystalline forms. Therefore, the scope of the present disclosure includes all amorphous or crystalline forms of the compounds disclosed herein. The term "polymorph" refers to a crystalline form of a compound (or a salt, hydrate, or solvate thereof) in a particular crystal packing arrangement. All polymorphs have the same elemental composition. Different crystalline forms generally have different X-ray diffraction patterns, infrared spectra, melting points, density, hardness, crystal shapes, optical and electrical properties, stability, and solubility. Recrystallization solvents, rate of crystallization, storage temperatures, and other factors may cause one crystalline form to dominate. Various polymorphs of a compound can be prepared by crystallization under different conditions.

[0509] As used herein, the term "isotopically labeled form" of a compound that contains an isotopic form of one or more atoms in the compound that is different from the naturally occurring isotopic distribution of the atom in nature. All isotopic forms are included as options, unless a specific isotopic form is indicated. An "isotopically label form" of a　compound　can be radiolabeled, that is, contain one or more radioactive isotopes, or can be labeled with non-radioactive isotopes such as for example, deuterium (2H or D), carbon-13 (13C), nitrogen-15 (15N), or the like. It will be understood that, in a　compound　where such isotopic substitution is made, the following atoms, where present, may vary, so that for example, any hydrogen may be　2H / D, any carbon may be　13C, or any nitrogen may be　15N, and that the presence and placement of such atoms may be determined by those skilled in the art.

[0510] As used herein, the term "prodrug" refers to substances that can be converted, under physiological conditions or through solvolysis, into the　compound　of the present disclosure having biological activity. The　prodrug　of the present disclosure is prepared by modifying the functional groups in the　compound, and the modification can be removed by conventional operations or removed in vivo, to produce the compound of the present disclosure. The　prodrug　includes a　compound　which is formed by connecting a hydroxyl group or amino group in the　compound　of the present disclosure to any group. When the　prodrug　of the　compound　of the present disclosure is administered to a mammalian individual, the　prodrug　is dissociated to form a free hydroxyl or amino group.

[0511] The term "pharmaceutically acceptable salt" refers to a salt which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and is commensurate with a reasonable benefit / risk ratio.

[0512] Certain compounds disclosed herein can exist in the form of salts, for example acid addition salts, or salts with organic or inorganic bases such as carboxylate, sulfonate and phosphate salts. All such salts are within the scope of this invention, and references to compounds disclosed herein include the salt forms of the compounds.

[0513] The salts of the present invention can be synthesized from the parent compound that contains a basic or acidic moiety by conventional chemical methods such as methods described in Pharmaceutical Salts: Properties, Selection, and Use, P. Heinrich Stahl (Editor), Camille G. Wermuth (Editor), ISBN: 3-90639-026-8, Hardcover, 388 pages, August 2002. Generally, such salts can be prepared by reacting the free acid or base form of the parent compound with the appropriate base or acid in water or in an organic solvent, or in a mixture of the two; generally, non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are used. Acid addition salts (e.g., mono - or di- salts) may be formed with a wide variety of acids, both inorganic and organic. Examples of acid addition salts include mono- or di- salts formed with an acid selected from the group consisting of acetic, 2,2-dichloroacetic, adipic, alginic, ascorbic (e.g. L-ascorbic), L-aspartic, benzenesulfonic, benzoic, 4-acetamidobenzoic, butanoic, (+) camphoric, camphor-sulfonic, (+)-(1S)-camphor-10-sulfonic, capric, caproic, caprylic, cinnamic, citric, cyclamic, dodecylsulfuric, ethane-1 ,2-disulfonic, ethanesulfonic, 2- hydroxyethanesulfonic, formic, fumaric, galactaric, gentisic, glucoheptonic, D-gluconic, glucuronic (e.g. D-glucuronic), glutamic (e.g. L-glutamic), a-oxoglutaric, glycolic, hippuric, hydrohalic acids (e.g. hydrobromic, hydrochloric, hydriodic), isethionic, lactic (e.g. (+)-L- lactic, (±)-DL-lactic), lactobionic, maleic, malic, (-)-L-malic, malonic, (±)-DL-mandelic, methanesulfonic, naphthalene-2-sulfonic, naphthalene-1, 5-disulfonic, 1-hydroxy-2-naphthoic, nicotinic, nitric, oleic, orotic, oxalic, palmitic, pamoic, phosphoric, propionic, pyruvic, L- pyroglutamic, salicylic, 4-amino-salicylic, sebacic, stearic, succinic, sulfuric, tannic, (+)-L- tartaric, thiocyanic, p-toluenesulfonic, undecylenic, valeric acids, and acylated amino acids.

[0514] One particular group of salts consists of salts formed from acetic, hydrochloric, hydriodic, phosphoric, nitric, sulfuric, citric, lactic, succinic, maleic, malic, isethionic, fumaric, benzenesulfonic, toluenesulfonic, methanesulfonic (mesylate), ethanesulfonic, naphthalenesulfonic, valeric, acetic, propanoic, butanoic, malonic, glucuronic and lactobionic acids. One particular salt is a hydrochloride salt.

[0515] Where the compounds disclosed herein contain an amine function, the compound may form quaternary ammonium salts, for example by reaction with an alkylating agent according to methods well known to those skilled in the art. Such quaternary ammonium compounds are within the scope of the compounds disclosed herein.

[0516] The compounds of the invention may exist as mono- or di- salts depending upon the pKa　of the acid from which the salt is formed.

[0517] It will be appreciated that for use in medicine the salts of the compounds disclosed herein should be pharmaceutically acceptable. Suitable pharmaceutically acceptable salts will be apparent to those skilled in the art. Pharmaceutically acceptable salts include those described by Berge, Bighley and Monkhouse, J. Pharm. Sci. 1977, 66, pp. 1-19. Such pharmaceutically acceptable salts include acid addition salts formed with inorganic acids e.g., hydrochloric, hydrobromic, sulfuric, nitric acid, phosphoric acid sulfuric acid, and perchloric acid and organic acids e.g., succinic, maleic, acetic, oxalic, malonic, fumaric, citric, tartaric, benzoic, p-toluenesulfonic, methanesulfonic or naphthalenesulfonic acid. Other salts e.g., oxalates or formates may be used, for example in the isolation of compounds disclosed herein and are included within the scope of this invention. However, salts that are not pharmaceutically acceptable may also be prepared as intermediate forms which may then be converted into pharmaceutically acceptable salts. Such non-pharmaceutically acceptable salts forms, which may be useful, for example, in the purification or separation of the compounds of the invention, also form part of the invention.

[0518] Salts formed using conventional methods in the art such as ion exchange are also included. Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate salts, and the like. Pharmaceutically acceptable salts derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1-4alkyl)4salts. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower alkyl sulfonate, and aryl sulfonate.

[0519] The compounds disclosed herein may form acid addition salts with one or more equivalents of the acid. The scope of the present invention includes all possible stoichiometric and non-stoichiometric forms.

[0520]

[0521] Preparation Methods

[0522] According to a further aspect of the present disclosure, provided is a process of preparing a compound of Formula (I), or a tautomer, stereoisomer, prodrug, crystal form, isotope variant, pharmaceutically acceptable salt, hydrate, or solvate thereof. The following schemes are examples of synthetic schemes that may be used to synthesize the compound of Formula (I). In the following schemes, reactive groups can be protected with protecting groups and de-protected by well-established techniques in the art. The compound of Formula (I) described in the present disclosure may be prepared by those skilled in the organic synthesis field by using a standard method, which is discussed below in detail.

[0523]

[0524] According to a further aspect of the present disclosure, a process of preparing the compound of Formula (I) as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, comprises any one of Processes A to E:

[0525] - Process A produces the compound of Formula (Id);

[0526] - Process B produces the compound of Formula (Ie);

[0527] - Process C produces the compound of Formula (If); and

[0528] - Process D produces the compound of Formula (Ig).

[0529]

[0530] Process A

[0531] Process A prepares the compound of Formula (Id), as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0532]

[0533] (i) preparing a compound of Formula (A-1):

[0534] ;

[0535] (A-1)

[0536]

[0537] (ii) reacting the compound of Formula (A-1) with a compound of Formula (A-2) to produce a compound of Formula (A-3):

[0538]

[0539] (A-2)

[0540] ;

[0541] (A-3)

[0542]

[0543] (iii) reacting the compound of Formula (A-3) with a compound of Formula (A-4) to produce a compound of Formula (A-5):

[0544]

[0545] (A-4)

[0546] ;

[0547] (A-5)

[0548]

[0549] (iv) reacting the compound of Formula (A-5) with a reducing agent (e.g., LiAlH4) to produce a compound of Formula (A-6):

[0550] ;

[0551] (A-6)

[0552]

[0553] (v) sulfonation of the compound of Formula (A-6) to produce a compound of Formula (A-7):

[0554] ;

[0555] (A-7)

[0556]

[0557] (vi) performing a ring formation of the compound of Formula (A-7) (e.g., reacting the compound of Formula (A-7) with POCl3) to produce a compound of Formula (A-8):

[0558] ; and

[0559] (A-8)

[0560]

[0561] (vii) reacting the compound of Formula (A-8) with a compound of (A-9) to produce the compound of Formula (Id):

[0562]

[0563] (A-9).

[0564] wherein ring A, ring B, W2, L, n, and q are as defined above;

[0565] Z1is halide (e.g., bromide);

[0566] Z2is halide or S(phenyl)2; and

[0567] Hal1is halide (e.g., chloride).

[0568]

[0569] In one embodiment, step (v) comprises:

[0570] (v-1) reacting the compound of Formula (A-6) with SOCl2to produce the compound of Formula (aa-1):

[0571] ; and

[0572] (aa-1)

[0573]

[0574] (v-2) reacting the compound of Formula (aa-1) with Na2SO3to produce the compound of Formula (A-7),

[0575] wherein ring A, ring B, W2, L, and q are as defined above.

[0576]

[0577] In one embodiment, an exemplary reaction scheme may be Scheme I shown below:

[0578] Scheme I

[0579]

[0580]

[0581] In one embodiment wherein the compound of Formula (A-1) is , step (i) comprises:

[0582]

[0583] (i-1) preparing a compound of Formula (aa-2):

[0584] ;

[0585] (aa-2)

[0586]

[0587] (i-2) reacting the compound of Formula (aa-2) with a compound of Formula (aa-3) to produce the compound of Formula (aa-4):

[0588] ;

[0589] (aa-3)

[0590] ;

[0591] (aa-4)

[0592]

[0593] (i-3) reacting the compound of Formula (aa-4) with a compound of Formula (aa-5) to produce the compound of Formula (aa-6):

[0594]

[0595] (aa-5)

[0596] ; and

[0597] (aa-6)

[0598]

[0599] (i-4) reacting the compound of Formula (aa-6) with H2in the presence of Raney-Ni to produce the compound of Formula (A-1),

[0600] wherein RL21, RL22, RL23, RL24, Ra1, and Ra2are as defined above; and

[0601] each of Hal2and Hal3is independently halide (for example bromide, and iodide).

[0602]

[0603] In one embodiment, an exemplary reaction scheme may be Scheme I-1 shown below:

[0604] Scheme I-1

[0605]

[0606]

[0607] In one embodiment wherein the compound of Formula (A-1) is , step (i) comprises:

[0608]

[0609] (i-1) preparing a compound of Formula (aa-7):

[0610] ;

[0611] (aa-7)

[0612]

[0613] (i-2) reacting the compound of Formula (aa-7) with a compound of Formula (aa-8) to produce the compound of Formula (aa-9):

[0614]

[0615] (aa-8)

[0616] ; and

[0617] (aa-9)

[0618]

[0619] (i-3) reacting the compound of Formula (aa-9) with H2in the presence of Raney-Ni to produce the compound of Formula (A-1),

[0620] wherein RL21, RL22, RL23, RL24, Ra2, and Ra4are as defined above.

[0621]

[0622] In one embodiment, an exemplary reaction scheme may be Scheme I-2 shown below:

[0623] Scheme I-2

[0624]

[0625]

[0626] In one embodiment wherein the compound of Formula (A-1) is , step (i) comprises:

[0627]

[0628] (i-1) preparing a compound of Formula (aa-10):

[0629] ;

[0630] (aa-10)

[0631]

[0632] (i-2) reacting the compound of Formula (aa-10) with BH3to produce a compound of Formula (aa-11):

[0633] ;

[0634] (aa-11)

[0635]

[0636] (i-3) reacting the compound of Formula (aa-11) with Dess-Martin periodinane (DMP) to produce a compound of Formula (aa-12):

[0637] ;

[0638] (aa-12)

[0639]

[0640] (i-4) reacting the compound of Formula (aa-12) with a compound of Formula (aa-13) to produce a compound of Formula (aa-14):

[0641]

[0642] (aa-13)

[0643] ;

[0644] (aa-14)

[0645]

[0646] (i-5) reacting the compound of Formula (aa-14) with a compound of Formula (aa-15) to produce a compound of Formula (aa-16):

[0647]

[0648] (aa-15)

[0649] ;

[0650] (aa-16)

[0651]

[0652] (i-6) reacting the compound of Formula (aa-16) with LiOH to produce a compound of Formula (aa-17):

[0653] ;

[0654] (aa-17)

[0655]

[0656] (i-7) reacting the compound of Formula (aa-17) with NH4Cl to produce a compound of Formula (aa-18):

[0657] ; and

[0658] (aa-18)

[0659]

[0660] (i-8) reacting the compound of Formula (aa-18) with BH3-Me2S to produce the compound of Formula (A-1),

[0661] wherein Ra1, and Ra2are as defined above; and

[0662] each of Hal5and Hal6is independently halide (for example bromide, and iodide).

[0663]

[0664] In one embodiment, an exemplary reaction scheme may be Scheme I-3 shown below:

[0665] Scheme I-3

[0666]

[0667]

[0668] In one embodiment wherein the compound of Formula (A-1) is

[0669] , step (i) comprises:

[0670]

[0671] (i-1) preparing a compound of Formula (aa-19):

[0672] ;

[0673] (aa-19)

[0674]

[0675] (i-2) reacting the compound of Formula (aa-19) with a compound of Formula (aa-20) to produce a compound of Formula (aa-21):

[0676]

[0677] (aa-20)

[0678] ;

[0679] (aa-21)

[0680]

[0681] (i-3) reacting the compound of Formula (aa-21) with bromomethylbenzene to produce a compound of Formula (aa-22):

[0682] ;

[0683] (aa-22)

[0684]

[0685] (i-4) reacting the compound of Formula (aa-21) with a compound of Formula (aa-23) to produce a compound of Formula (aa-24):

[0686]

[0687] (aa-23)

[0688] ;

[0689] (aa-24)

[0690]

[0691] (i-5) reacting the compound of Formula (aa-24) with H2gas in a presence of Pd / C catalyst to produce a compound of Formula (aa-25):

[0692] ;

[0693] (aa-25)

[0694]

[0695] (i-6) performing a ring formation of the compound of Formula (aa-24) to produce a compound of Formula (aa-26):

[0696] ;

[0697] (aa-26)

[0698]

[0699] (i-7) reacting the compound of Formula (aa-26) with LiAlH4to produce a compound of Formula (aa-27):

[0700] ;

[0701] (aa-27)

[0702]

[0703] (i-8) reacting the compound of Formula (aa-27) with methylsulfonyl methanesulfonate to produce a compound of Formula (aa-28):

[0704] ;

[0705] (aa-28)

[0706]

[0707] (i-9) reacting the compound of Formula (aa-28) with tert-butyl N-tert-butoxycarbonylcarbamate to produce a compound of Formula (aa-29):

[0708] ; and

[0709] (aa-29)

[0710]

[0711] (i-10) reacting the compound of Formula (aa-29) with HCl / dioxane to produce the compound of Formula (A-1),

[0712] wherein RL11, and Ra2are as defined above; and

[0713] Hal2is halide (for example bromide).

[0714]

[0715] In one embodiment, an exemplary reaction scheme may be Scheme I-4 shown below:

[0716] Scheme I-4

[0717] .

[0718]

[0719] Process B

[0720] Process B prepares the compound of Formula (Ie), as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0721]

[0722] (i) preparing a compound of Formula (B-1):

[0723] ;

[0724] (B-1)

[0725]

[0726] (ii) reacting the compound of Formula (B-1) with 1-(chloromethyl)-4-methoxy-benzene to produce a compound of Formula (B-2):

[0727] ;

[0728] (B-2)

[0729]

[0730] (iii) reacting the compound of Formula (B-2) with a compound of Formula (B-3) to produce a compound of Formula (B-4):

[0731]

[0732] (B-3)

[0733] ;

[0734] (B-4)

[0735]

[0736] (iv) reacting the compound of Formula (B-4) with H2gas to produce a compound of Formula (B-5):

[0737]

[0738] (B-5)

[0739]

[0740] (v) reacting the compound of Formula (B-5) with a compound of Formula (B-6) to produce a compound of Formula (B-7):

[0741]

[0742] (B-6)

[0743] ;

[0744] (B-7)

[0745]

[0746] (vi) reacting the compound of Formula (B-7) with a compound of Formula (B-8) to produce a compound of Formula (B-9):

[0747]

[0748] (B-8)

[0749]

[0750] (B-9)

[0751]

[0752] (vii) reacting the compound of Formula (B-9) with NaBH4to produce a compound of Formula (B-10):

[0753] ;

[0754] (B-10)

[0755]

[0756] (viii) reacting the compound of Formula (B-10) with SOCl2to produce a compound of Formula (B-11):

[0757] ;

[0758] (B-11)

[0759]

[0760] (ix) reacting the compound of Formula (B-11) with disodium / sulfite to produce a compound of Formula (B-12):

[0761] ;

[0762] (B-12)

[0763]

[0764] (x) performing a ring formation of Formula (B-12) to produce a compound of Formula (B-13):

[0765] ;

[0766] (B-13)

[0767]

[0768] (xi) reacting the compound of Formula (B-13) with 2-bromoethyl(diphenyl)sulfonium / trifluoromethanesulfonate to produce a compound of Formula (B-14):

[0769] ; and

[0770] (B-14)

[0771]

[0772] (xii) reacting the compound of Formula (B-14) with NaOAc to produce the compound of Formula (Ie),

[0773] wherein ring B, L, W1, and W2are as defined above; and

[0774] each of Hal8, Hal9, and Hal10is independently halide (e.g., bromide, and chloride).

[0775]

[0776] In one embodiment, an exemplary reaction scheme may be Scheme II shown below:

[0777] Scheme II

[0778]

[0779]

[0780]

[0781] Process C

[0782] Process C prepares the compound of Formula (If), as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0783]

[0784] (i) preparing a compound of Formula (C-1):

[0785] ;

[0786] (C-1)

[0787]

[0788] (ii) reacting the compound of Formula (C-1) with 1-(chloromethyl)-4-methoxy-benzene to produce a compound of Formula (C-2):

[0789] ;

[0790] (C-2)

[0791]

[0792] (iii) reacting the compound of Formula (C-2) with a compound of Formula (C-3) to produce a compound of Formula (C-4):

[0793]

[0794] (C-3)

[0795] ;

[0796] (C-4)

[0797]

[0798] (iv) reacting the compound of Formula (C-4) with H2gas to produce a compound of Formula (C-5):

[0799] ;

[0800] (C-5)

[0801]

[0802] (v) reacting the compound of Formula (C-5) with a compound of Formula (C-6) to produce a compound of Formula (C-7):

[0803]

[0804] (C-6)

[0805] ;

[0806] (C-7)

[0807]

[0808] (vi) reacting the compound of Formula (C-7) with a compound of Formula (C-8) to produce a compound of Formula (C-9):

[0809]

[0810] (C-8)

[0811] ;

[0812] (C-9)

[0813]

[0814] (vii) reacting the compound of Formula (C-9) with LiAlH4to produce a compound of Formula (C-10):

[0815]

[0816] (C-10)

[0817]

[0818] (viii) reacting the compound of Formula (C-10) with SOCl2to produce a compound of Formula (C-11):

[0819] ;

[0820] (C-11)

[0821]

[0822] (ix) reacting the compound of Formula (C-11) with disodium / sulfite to produce a compound of Formula (C-12):

[0823]

[0824] ;

[0825] (C-12)

[0826]

[0827] (x) performing a ring formation of Formula (C-12) to produce a compound of Formula (C-13):

[0828] ;

[0829] (C-13)

[0830]

[0831] (xi) reacting the compound of Formula (C-13) with 2-bromoethyl(diphenyl)sulfonium / trifluoromethanesulfonate to produce a compound of Formula (C-14):

[0832] ; and

[0833] (C-14)

[0834]

[0835] (xii) reacting the compound of Formula (C-14) with trifluoroacetic acid (TFA) to produce a compound of Formula (If),

[0836] wherein ring B, L, W1, and W2are as defined above; and

[0837] each of Hal11, and Hal12is independently halide (e.g., bromide, and chloride).

[0838]

[0839] In one embodiment, an exemplary reaction scheme may be Scheme III shown below:

[0840] Scheme III

[0841]

[0842]

[0843]

[0844] Process D

[0845] Process D prepares the compound of Formula (Ig), as herein defined or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate or solvate thereof, which comprises:

[0846]

[0847] (i) preparing a compound of Formula (D-1):

[0848] ;

[0849] (D-1)

[0850]

[0851] (ii) reacting the compound of Formula (D-1) with a compound of Formula (D-2) to produce a compound of Formula (D-3):

[0852] ;

[0853] (D-2)

[0854] ;

[0855] (D-3)

[0856]

[0857] (iii) reacting the compound of Formula (D-3) with a compound of Formula (D-4) to produce a compound of Formula (D-5):

[0858]

[0859] (D-4)

[0860] ;

[0861] (D-5)

[0862]

[0863] (iv) reacting the compound of Formula (D-5) with 4-Dimethylaminopyridine (DMAP) / TEA / Boc2O to produce a compound of Formula (D-6):

[0864]

[0865] (D-6)

[0866]

[0867] (v) reacting the compound of Formula (D-6) with K2CO3to produce a compound of Formula (D-7):

[0868] ;

[0869] (D-7)

[0870]

[0871] (vi) reacting the compound of Formula (D-7) with a compound of Formula (D-8) to produce a compound of Formula (D-9):

[0872] ;

[0873] (D-8)

[0874] ;

[0875] (D-9)

[0876]

[0877] (vii) reacting the compound of Formula (D-9) with Pd(OAc)2 / Bis(diphenylphosphino)ferrocene (DPPF) to produce a compound of Formula (D-10):

[0878] ;

[0879] (D-10)

[0880]

[0881] (viii) reacting the compound of Formula (D-10) with LiAlH4to produce a compound of Formula (D-11):

[0882] ;

[0883] (D-11)

[0884]

[0885] (ix) reacting the compound of Formula (D-11) with SOCl2to produce a compound of Formula (D-12):

[0886] ;

[0887] (D-12)

[0888]

[0889] (x) reacting the compound of Formula (D-12) with Na2SO3to produce a compound of Formula (D-13):

[0890] ;

[0891] (D-13)

[0892]

[0893] (xi) performing a ring formation of the compound of Formula (D-13) to produce a compound of Formula (D-14):

[0894] ; and

[0895] (D-14)

[0896]

[0897] (xii) reacting the compound of Formula (D-14) with 2-bromoethyl(diphenyl)sulfonium;trifluoromethanesulfonate to produce a compound of Formula (Ig),

[0898] wherein ring A, ring B, L, q, and W2are as defined above;

[0899] Halwis halogen (e.g., fluoro, chloro, bromo, and iodo); and

[0900] each of Hal13, Hal14, and Hal15is independently halogen (e.g., chloro, bromo).

[0901]

[0902] In one embodiment, an exemplary reaction scheme may be Scheme IV shown below:

[0903] Scheme IV

[0904]

[0905]

[0906]

[0907] Therapeutic utilities

[0908] The terms "treat", "treating", "treatment" and the like refer to a course of action (such as administering an inhibitor of USP1 or a pharmaceutical composition comprising same) initiated after a disease, disorder or condition, or a symptom thereof, has been diagnosed, observed, and the like so as to eliminate, reduce, suppress, mitigate, or ameliorate, either temporarily or permanently, at least one of the underlying causes of a disease, disorder, or condition afflicting a subject, or at least one of the symptoms associated with a disease, disorder, condition afflicting a subject. Thus, "treatment" may also refer to inhibiting (e.g., arresting the development or further development of the disease, disorder or condition or clinical symptoms association therewith) an active disease.

[0909] The terms "prevent", "preventing", "prevention" and the like refer to a course of action (such as administering a USP1 inhibitor or a pharmaceutical composition comprising same) initiated in a manner (e.g., prior to the onset of a disease, disorder, condition or symptom thereof) so as to prevent, suppress, inhibit or reduce, either temporarily or permanently, a subject's risk of developing a disease, disorder, condition or the like (as determined by, for example, the absence of clinical symptoms) or delaying the onset thereof, generally in the context of a subject predisposed to having a particular disease, disorder or condition. In certain instances, the terms also refer to slowing the progression of the disease, disorder or condition or inhibiting the progression of the disease, disorder or condition such that it does not reach a harmful or otherwise undesired state.

[0910] The terms "inhibiting" and "reducing," or any variation of these terms in relation of USP1, may refer to any measurable decrease or complete inhibition to achieve a desired result. For example, there may be a decrease in USP1 activity of about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or more, compared to a control group. The term "about" as used herein means variations within ± 20%, preferably, within ± 10%, more preferably within ± 5% of a given value.

[0911] "Disease", "disorder" and "condition" are used interchangeably herein.

[0912] The present disclosure provides a compound that prevents or treats a disease or disorder mediated by USP1 or a disease or disorder in which USP1 activity is implicated. The present disclosure also provides a compound that selectively inhibits USP1 enzyme activityin vitroorin vivo.

[0913] In some embodiments, the disease or disorder mediated by USP1 is cancer. In some embodiments, the disease or disorder mediated by USP1 is a hematological cancer, a lymphatic cancer, and a DNA damage repair pathway deficient cancer. In some embodiments, the cancer comprises cancer cells with a mutation in genes encoding BRCA1 or BRCA2. In some embodiments, the cancer comprises cancer cells with a mutation in a gene encoding p53. In some embodiments, the mutation in the gene encoding p53 is a germline mutation. In some embodiments, the mutation in the gene encoding p53 is a somatic mutation. In some embodiments, the cancer comprises cancer cells with a loss of function mutation in the gene encoding p53. In some embodiments, the cancer is selected from the group consisting of lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; skin cancer including melanoma, kidney cancer (Garc a-Santisteban et al. Molecular Cancer 2013, 12:91), colon cancer, osteosarcoma (Int J Biol Sci. 2022; 18(8): 3122-3136.), triple negative breast cancer (Cancers (Basel). 2020 Nov; 12(11): 3090), pancreatic cancer (iScience. 2018 Mar 23; 1: 72-86), bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; and uterine cancer.

[0914] In a cancer treatment, the therapeutically effective amount of the compound of Formula (I) provided herein is an amount sufficient to provide therapeutic benefits during the course of the treatment, or to delay or minimize one or more symptoms associated with cancer. In a cancer treatment, the therapeutically effective amount of a compound is the amount of the therapeutic agent that, when used alone or in combination with other therapies, provides such therapeutic benefits during the course of the treatment.

[0915] Effective amounts of the compound of the present disclosure vary depending upon many different factors, including means of administration, target site, physiological state of the patient, whether the patient is human or an animal, other medications administered, whether treatment is prophylactic or therapeutic, as well as the specific activity of the composition itself and its ability to elicit the desired response in the individual. In the context of this disclosure, the patient can be a human or non-human mammal. Typically, dosage regimens are adjusted to provide an optimum therapeutic response, i.e., to optimize safety and efficacy. Accordingly, a therapeutically effective amount is also one of which any undesired collateral effects are outweighed by the beneficial effects of administering the compound as described herein.

[0916]

[0917] Pharmaceutical compositions

[0918] The terms "combination", "combined", and related terms refer to the simultaneous, separate or sequential administration of two or more therapeutic agents or therapies. For example, the compound disclosed herein may be administered with another therapeutic agent or therapy simultaneously or sequentially in separate unit dosage forms, or together in a single unit dosage form. The another therapy may be radiotherapy. The another therapeutic agent may be an anti-cancer agent. The anti-cancer agent may include DNA damage response (DDR) targeting anti-cancer agents. The DNA damage response (DDR) is a collective term for the plethora of different intra- and inter-cellular signaling events and　enzyme　activities that result from the induction and detection of DNA damage. There are at least three　key aspects of DDR that are different in cancers compared with normal cells, which in turn make DDR an attractive source for drug targets that can (and indeed currently are) being exploited to generate new cancer therapies. Loss of one or more DDR pathways, increased replication stress, and higher levels of endogenous DNA damage are all differentiating aspects of cancer DDR that can be targeted therapeutically. A number of anti-cancer agents targeting DDR have been known and developed, e.g., PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (e.g., MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide), etc. (see Mark　J.　O'Connor, Molecular Cell 60, November 19, 2015, p. 547-560, Choi et al., Int J Mol Sci.　2022 Feb; 23(3): 1701). The compound disclosed herein also belongs to DDR targeting agents.

[0919] In some embodiment, provided is a pharmaceutical composition including the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, and a pharmaceutical acceptable carrier, wherein the composition may be administered simultaneously, separately or sequentially with additional DDR targeting anti-cancer agent described above.

[0920] In some embodiment, provided is a method of treating or preventing diseases or disorders mediated by USP1, in a subject, comprising administering to the subject the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, wherein the method further comprises administering additional DDR targeting anti-cancer agent described above to the subject.

[0921] In some embodiment, provided is a kit or product comprising:

[0922] - a first pharmaceutical composition or dosage form comprising the compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof and, optionally, one or more pharmaceutically acceptable carriers; and

[0923] - a second pharmaceutical composition or dosage form comprising additional DDR targeting anti-cancer agent described above, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof and, optionally, one or more pharmaceutically acceptable carriers.

[0924] In some embodiment, the kit or product is for use in a method of treating and / or preventing diseases or disorders mediated by USP1. In some embodiment, the first pharmaceutical composition or dosage form may be administered simultaneously, separately or sequentially with second pharmaceutical composition or dosage form. In some embodiment, the kit or product may further comprise a package insert comprising an instruction for simultaneous, sequential or separate use in the treatment and / or prevention of diseases or disorders mediated by USP1.

[0925] The present disclosure further relates to a pharmaceutical composition, comprising a pharmaceutically effective amount of one or more of the compounds disclosed herein, and a pharmaceutically acceptable carrier(s) and / or excipient(s). The composition may further comprise at least one of additional therapeutic agents in amounts effective for achieving the treatment or prevention of diseases or disorders disclosed herein. Pharmaceutically acceptable carriers and excipients are well known in the art, and the choice of carriers and excipients will to a large extent depend on factors such as mode of administration, their effects on solubility and stability, and the nature of dosage form.

[0926]

[0927] Treatment method

[0928] In another aspect, the present disclosure provides a method of treating or preventing diseases or disorders, such as diseases or disorders mediated by USP1, in a subject in need of treatment or prevention, comprising administering to the subject at least one compound disclosed herein, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof, or a pharmaceutical composition disclosed herein.

[0929] The terms "human", "patient" or "subject" are used interchangeably. A "subject" to which administration is contemplated includes, but is not limited to, humans (i.e., a male or female of any age group, e.g., a pediatric subject (e.g., infant, child, adolescent) or adult subject (e.g., young adult, middle-aged adult or senior adult)) and / or a non-human animal, e.g., a mammal such as primates (e.g., cynomolgus monkeys, rhesus monkeys), cattle, pigs, horses, sheep, goats, rodents, cats, and / or dogs. In some embodiments, the subject is a human. In some embodiments, the subject is a non-human animal.

[0930]

[0931] Administration

[0932] The pharmaceutical composition of the present disclosure can be administered via various routes, including, but not limited to, oral, parenteral (injected), (e.g., intravenous, subcutaneous, intramuscular, intravascular administration, or infusion), sublingual, topical, transdermal, ocular, rectal, nasal, and vaginal administration.

[0933] The pharmaceutical composition provided herein is administered in a pharmaceutically effective amount. For example, the pharmaceutically effective amount of the pharmaceutical composition may be in the range of about 0.01 mg to about 500 mg / kg of body weight, or about 10 mg to about 500 mg / kg of body weight. In one embodiment, the amount may be in the range of about 0.1 mg to about 250 mg / kg of body weight, or about 0.1 mg to about 10 mg / kg of body weight, or about 0.1 mg to about 1 mg / kg of body weight. In another embodiment, the amount be in the range of about 1 mg to about 100 mg / kg of body weight, preferably, about 10 mg to about 100 mg / kg of body weight. The amount of the composition to be administered will typically be determined by a physician, in light of the relevant circumstances, including the condition to be treated, the chosen route of administration, the actual compound to be administered, the age, weight, and response of the individual patient, the severity of the patient's symptoms, and the like.

[0934]

[0935] Formulation

[0936] The pharmaceutical composition may, for example, be in a form suitable for oral administration such as a tablet, capsule, pill, powder, sustained release formulations, solution, suspension, for parenteral injection such as a sterile solution, suspension or emulsion, for topical administration such as an ointment or cream, or for rectal administration such as a suppository. The pharmaceutical composition will include a conventional pharmaceutical carrier or excipient, and a compound of the present disclosure as an active ingredient. In addition, it may include other medicinal or pharmaceutical agents, carriers, adjuvants, etc.

[0937] Exemplary parenteral administration forms include solutions or suspensions of active compounds in sterile aqueous solutions, for example, aqueous propylene glycol or dextrose solutions. Such dosage forms can be suitably buffered, if desired. Suitable pharmaceutical carriers include inert diluents or fillers, water and various organic solvents. The pharmaceutical compositions may, if desired, contain additional ingredients such as flavorings, binders, excipients and the like. For oral administration, tablets containing various excipients, such as citric acid may be employed together with various disintegrants such as starch, alginic acid and certain complex silicates and with binding agents such as sucrose, gelatin and acacia. Additionally, lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often useful for tableting purposes. Solid compositions of a similar type may also be employed in soft and hard filled gelatin capsules. Preferred materials include lactose or milk sugar and high molecular weight polyethylene glycols. When aqueous suspensions or elixirs are desired for oral administration, the active compound therein may be combined with various sweetening or flavoring agents, coloring matters or dyes and, if desired, emulsifying agents or suspending agents, together with diluents such as water, ethanol, propylene glycol, glycerin, or combinations thereof. Methods of preparing various pharmaceutical compositions with a specific amount of active compound are known, or will be apparent, to those skilled in the art.

[0938]

[0939] Dosage

[0940] The pharmaceutical composition of the present disclosure may be administered in a single dose or in multiple doses. Dosing may occur one time, two times, three times, four times, five times, six times, or more than six times per day. Dosing may occur once a month, once every two weeks, once a week, or once every other day. In some cases, continuous dosing is achieved and maintained as long as necessary. In some embodiments, the pharmaceutical composition of the present disclosure is administered for more than 1, 2, 3, 4, 5, 6, 7, 14, or 28 days. In some embodiments, the pharmaceutical composition of the present disclosure is administered for less than 28, 14, 7, 6, 5, 4, 3, 2, or 1 day. In some embodiments, the pharmaceutical composition of the present disclosure is administered chronically on an ongoing basis.

[0941]

[0942] It is noted that the compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention should be understood to applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed herein (including any accompanying claims, and abstract), and / or all of the steps of any method or process disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed herein (including any accompanying claims, and abstract), or to any novel one, or any novel combination, of the steps of any method or process disclosed.

[0943] The contents of the articles and documents referred to herein are incorporated herein by reference in its entirety as if all of their contents are described in detail herein.

[0944]

[0945]

[0946] EXAMPLE

[0947]

[0948] The present disclosure will be further described below with descriptions of specific examples. It should be understood that the following examples are only used to illustrate the present disclosure and not to limit the scope of the present disclosure. The experimental methods without specific conditions used in the following examples are generally performed under conventional conditions or conditions recommended by the manufacturer. Unless otherwise stated, parts and percentages are parts by weight and weight percent.

[0949] Generally, in the preparation process, each reaction is carried out in an inert solvent at a temperature from room temperature to reflux temperature (e.g., 0 ℃ to 100 ℃, or alternatively 0 ℃ to 80 ℃). The reaction time is usually 0.1-60 hours, or alternatively 0.5-24 hours.

[0950]

[0951] Abbreviations

[0952] The abbreviations as used herein have the following meanings:

[0953] EtOAc: Ethyl acetate

[0954] Brine: aqueous sodium chloride

[0955] Na2SO4: Sodium sulfate

[0956] Na2SO3: Sodium sulfite

[0957] DCM: Dichloromethane

[0958] LCMS: Liquid chromatography-mass spectrometry

[0959] HPLC: High-performance liquid chromatography

[0960] Cs2CO3: Cesium carbonate

[0961] POCl3: Phosphorus(V) oxychloride

[0962] SOCl2: Thionyl chloride

[0963] TEA: Triethylamine

[0964] DIEA: N,N-Diisopropylethylamine

[0965] NaOAc: Sodium acetate

[0966] DMF: Dimethylformamide

[0967] THF: Tetrahydrofuran

[0968] HFIP: Hexafluoro-2-propanol

[0969] Na2CO3: Sodium carbonate

[0970] K3PO4: Potassium phosphate

[0971] LiAlH4: Lithium aluminum hydride

[0972] NaBH4: Sodium borohydride

[0973] Pd(pph3)4: Tetrakis(triphenylphosphine)palladium(0)

[0974] NBS:N-Bromosuccinimide

[0975] DMAP: 4-(Dimethylamino)pyridine

[0976] t-BuOH: tert-butyl alcohol

[0977] Boc2O: Di-tert-butyl dicarbonate

[0978] CaCl2: Calcium chloride

[0979] NH4Cl: Ammonium chloride

[0980] HCl: Hydrochloric acid

[0981] ACN: Acetonitrile

[0982] DPPF: 1,1'-Ferrocenediyl-bis(diphenylphosphine)

[0983] DEAD: Diethyl azodicarboxylate

[0984] BOP: Benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate

[0985] HPLC: High-performance liquid chromatography

[0986]

[0987] Materials and Methods

[0988] Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless otherwise described. All reactions were performed at RT unless otherwise stated. Flash column chromatography was carried out using pre-packed columns filled with Merck flash silica gel 60 (40-63 μm) or C18 flash silica on an ISCO Combiflash Nextgen or a Biotage Selekt.

[0989] Unless otherwise noted, all reagents were without further purification.1H-NMR spectra were obtained in DMSO-d6orCDCl3at room temperature on a Bruker 400 MHz instrument. When more than one conformer was detected, the chemical shifts for the most abundant one was reported. Chemical shifts of1H NMR spectra were recorded in parts per million (ppm) on the δ scale from an internal standard of residual solvent. Splitting patterns are designed as (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constants (Hz), and integrated and often tabulated; LC-MS conditions are described below:

[0990]

[0991] LCMS Method A：

[0992] LCMS Column: SHIMADZU Xtimate C18 2.1*30 mm, 3um

[0993] Mobile Phase: Solvent A: water (4L)+TFA (1.5mL)

[0994] Solvent B: acetonitrile (4L)+TFA(0.75mL)

[0995] Flow Rate: 0.8 mL / min

[0996] Run time: gradient 10%-80% (solvent B) over 6 minutes and holding at 80% for 0.5 minutes

[0997] Temperature: 50 ℃

[0998]

[0999] LCMS Method B：

[1000] LCMS Column: SHIMADZU Nano Chrom 120 C18 3.0*30 mm, 3um

[1001] Mobile Phase: Solvent A: water (4L)+TFA (1.5mL)

[1002] Solvent B: acetonitrile (4L)+TFA(0.75mL)

[1003] Flow Rate: 0.8 mL / min

[1004] Run time: gradient 10%-80% (solvent B) over 6 minutes and holding at 80% for 0.5 minutes

[1005] Temperature: 50 ℃

[1006]

[1007] LCMS Method C：

[1008] LCMS Column: SHIMADZU Xtimate C18 2.1*30 mm, 3um

[1009] Mobile Phase: Solvent A: water (4L)+TFA (1.5mL)

[1010] Solvent B: acetonitrile (4L)+TFA(0.75mL)

[1011] Flow Rate: 0.8 mL / min

[1012] Run time: gradient 30%-90% (solvent B) over 6 minutes and holding at 90% for 0.5 minutes

[1013] Temperature: 50 ℃

[1014]

[1015] LCMS Method D：

[1016] LCMS Column: SHIMADZU Nano Chrom 120 C18 3.0*30 mm, 3um

[1017] Mobile Phase: Solvent A: water (4L)+TFA (1.5mL)

[1018] Solvent B: acetonitrile (4L)+TFA(0.75mL)

[1019] Flow Rate: 0.8 mL / min

[1020] Run time: gradient 30%-90% (solvent B) over 6 minutes and holding at 90% for 0.5 minutes

[1021] Temperature: 50 ℃

[1022]

[1023] ExperimentalProcedure:

[1024] Int 1 : 2-(4-(chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole

[1025]

[1026]

[1027] Step a.To a mixture of 3,3-dibromo-1,1,1-trifluoro-propan-2-one (10.00 g, 37.06 mmol) in H2O (40 mL) was added NaOAc (6.03 g, 73.45 mmol). The mixture was stirred at 100 ℃ under an N2atmosphere for 1 h. The mixture was cooled to 0 ℃. 4-(hydroxymethyl)-benzaldehyde (5 g, 36.72 mmol) and NH3·H2O (14 M) in MeOH (200 mL) were added to the above-mentioned mixture at 0 ℃. The mixture was stirred at 20 ℃ under an N2atmosphere for 12 h. LCMS showing the desired mass was detected. The mixture was diluted with H2O (150 mL), extracted with EtOAc (300 mL Х 3). The combined organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to produce a residue. The residue was slurried with DCM (100 mL) at 20 ℃ for 1 h. The mixture was filtered, the filter cake was concentrated under reduced pressure to produce [4-[4-(trifluoromethyl)-1H-imidazol-2-yl]phenyl]methanol (5.2 g, 19.75 mmol, 53.79% yield, 92% purity) as a yellow solid.

[1028] MS (ESI) m / z = 242.8 [M+H]+;1H NMR (DMSO-d6) δ= 13.13 (br s, 1H), 7.93 (d,J= 8.4 Hz, 2H), 7.90 (s, 1H), 7.43 (d,J= 8.4 Hz, 2H), 5.28 (t,J= 5.6 Hz, 1H), 4.55 (d,J= 5.6 Hz, 2H).

[1029] Step b.A mixture of [4-[4-(trifluoromethyl)-1H-imidazol-2-yl]phenyl]methanol (1 g, 4.13 mmol), 2-iodopropane (2.11 g, 12.39 mmol, 1.24 mL) and Cs2CO3(2.69 g, 8.26 mmol) in DMF (50 mL) was degassed and purged with N23 times, and then the mixture was stirred at 120 ℃ for 4 h under an N2atmosphere. LCMS showing the desired mass was detected. The mixture was diluted with H2O (80 mL), extracted with EtOAc (80 mL Х 3). The combined organic layer was washed with brine (80 mL), dried over anhydrous Na2SO4and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography on silica gel eluting with 0~60% ethyl acetate in petroleum ether to produce [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methanol (1.1 g, 3.60 mmol, 87.16% yield, 93% purity) as a yellow solid.

[1030] MS (ESI) m / z = 284.9 [M+H]+;1H NMR (DMSO-d6) δ = 8.16 (s, 1H), 5.45 (t,J =5.6 Hz, 1H), 4.54 (d,J =5.6 Hz, 2H), 4.46-4.42 (m, 1H), 1.40 (d,J= 6.8 Hz, 6H).

[1031] Step c.To a mixture of [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methanol (1.1 g, 3.87 mmol) in DCM (40 mL) was added SOCl2(690.53 mg, 5.80 mmol, 421.57 μL) at 0 ℃. The mixture was stirred at 20℃ for 2 h under an N2atmosphere. LCMS showing the desired mass was detected. The reaction mixture was concentrated under reduced pressure to produce 2-(4-(chloromethyl)phenyl)-1-isopropyl-4-(trifluoromethyl)-1H-imidazole (650 mg, 2.06 mmol, 53.27% yield, 96% purity) as a yellow solid.

[1032] MS (ESI) m / z = 302.9 [M+H]+;1H NMR (DMSO-d6) δ = 8.19 (s, 1H), 7.59 (s, 4H), 4.85 (s, 2H), 4.53-4.44 (m, 1H), 1.41 (d,J= 6.8 Hz, 6H).

[1033]

[1034] Int 2 : [4-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]methanamine

[1035]

[1036] Step a.A solution of 4-hydrazinobenzonitrile;hydrochloride (15 g, 88.44 mmo) and 1,1,1-trifluoropentane-2,4-dione (13.63 g, 88.44 mmol, 10.70 mL) in HFIP (80 mL) was cooled to 0 ℃. To the solution was added a solution of TEA (17.90 g, 176.88 mmol, 24.62 mL) in HFIP (20 mL) dropwise over 10 min. The mixture was stirred at 20 ℃ for 2 h. LCMS showing the desired mass was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 3 / 1) to produce 4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]benzonitrile (11 g, 40.72 mmol, 46.05% yield, 93% purity) as a yellow oil.

[1037] MS (ESI) m / z = 252.1 [M+H]+.

[1038] Step b.Under an Ar atmosphere, Raney-Ni (1.50 g, 17.52 mmol) was added to a solution of 4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]benzonitrile (11 g, 43.79 mmol) in NH3.H2O (20 mL) and MeOH (100 mL). Then the mixture was degassed and purged with Ar 3 times and H23 times. The mixture was stirred under an H2atmosphere (45 Psi) at 25 ℃ for 16 h. LCMS showing the desired mass was detected. The reaction mixture was filtered through a celite and the filtrate cake was washed with MeOH (100 mL Х 3), and the combined organic layers were concentrated under reduced pressure to produce [4-[5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]phenyl]methanamine (7 g, crude) as a yellow oil.

[1039] MS (ESI) m / z = 239.1 [M-NH2+H]+.

[1040]

[1041] Int 3 : [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methanamine

[1042]

[1043] Step a.A mixture of 3,3-dibromo-1,1,1-trifluoro-propan-2-one (51.45 g, 190.65 mmol), NaOAc (15.64 g, 190.65 mmol) in H2O (6 mL) was degassed and purged 3 times with N2, then the mixture was stirred at 100 ℃ for 1 h under an N2atmosphere. The mixture was cooled to 20 ℃. To the mixture 4-formylbenzonitrile (25 g, 190.65 mmol) and NH3·H2O (14 M, 163.41 mL) in MeOH (300 mL) were added and the mixture stirred at 100 ℃ for 1 h. LCMS showing the desired mass was detected. The reaction mixture was quenched by the addition of H2O (100 mL), then extracted with EtOAc (50 mL Х 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 1 / 1) to produce 4-[4-(trifluoromethyl)-1H-imidazol-2-yl]benzonitrile (30 g, 87.28 mmol, 45.78% yield, 69% purity) as a yellow solid.

[1044] MS (ESI) m / z = 279.2 [M+H]+;1H NMR (DMSO-d6)δ= 13.53 (s, 1H), 8.13 (d,J= 7.6 Hz, 2H), 8.06 (s,1H), 7.96 (d,J= 7.6 Hz, 2H).

[1045] Step b.A mixture of 4-[4-(trifluoromethyl)-1H-imidazol-2-yl]benzonitrile (30 g, 126.49 mmol), 2-iodopropane (64.50 g, 379.46 mmol, 37.88 mL), Cs2CO3(82.42 g, 252.97 mmol) in DMF (300 mL) was degassed and purged 3 times with N2, and the mixture was stirred at 120 ℃ for 4 h under an N2atmosphere. LCMS showing the desired mass was detected. The reaction mixture was diluted with water (100 mL), then extracted with EtOAc (200 mL Х 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate = 3 / 1) to produce 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]benzonitrile (20 g, 55.15 mmol, 43.60% yield, 77% purity) as a yellow oil.

[1046] MS (ESI) m / z = 280.2 [M+H]+;1H NMR (DMSO-d6)δ= 8.28 (s, 1H), 8.00 (d,J= 8.4 Hz, 2H), 7.79 (d,J= 8.4 Hz, 2H), 4.48-4.51 (m, 1H), 1.42 (d,J= 6.8 Hz, 6H).

[1047] Step c.To a mixture of 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]benzonitrile (20 g, 71.62 mmol) in NH3·H2O (60 mL) and MeOH (200 mL) was added Raney-Ni (2.45 g, 28.65 mmol), then the mixture was degassed and purged 3 times with Ar and 3 times with H2, and then the mixture was stirred at 25 ℃ for 72 h under an H2atmosphere at 50 psi. LCMS showing the desired product was detected. The reaction mixture was filtered and washed with MeOH (50 mL), and the combined filtrates were concentrated under reduced pressure to produce [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methanamine (15 g, crude) as a yellow oil.

[1048] MS (ESI) m / z = 284.0 [M+H]+.

[1049]

[1050] Example 1

[1051] 6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1'-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl] spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide

[1052]

[1053] Step a.To a solution of Int 3 and methyl 2,4-dichloropyrimidine-5-carboxylate (5 g, 24.15 mmol) in DMF (20 mL) was added DIEA (9.36 g, 72.46 mmol, 12.62 mL) at -78 ℃, and then the mixture was stirred at -78 °C for 2 h. LCMS showing the desired mass was observed. The reaction mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to produce methyl 2-chloro-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]amino]pyrimidine-5-carboxylate (3.5 g, 6.94 mmol, 28.74% yield, 90% purity) as a yellow solid.

[1054] MS (ESI) m / z = 454.0 [M+H]+;1H NMR (DMSO-d6)δ= 9.06 (t,J= 6.4 Hz, 1H), 8.66 (s, 1H), 8.17 (d,J= 1.2 Hz, 1H), 7.53 (d,J= 7.6 Hz, 2H), 7.48 (d,J= 7.6 Hz, 2H), 4.78 (d,J= 6.0 Hz, 2H), 4.62-4.45 (m, 1H), 3.87 (s, 3H), 1.40 (d,J= 6.8 Hz, 6H).

[1055] Step b.To a solution of methyl 2-chloro-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]amino]pyrimidine-5-carboxylate (3.5 g, 7.71 mmol) and (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boronic acid (1.80 g, 9.25 mmol) was added ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (502.62 mg, 771.19 μmol), K3PO4(3.27 g, 15.42 mmol) in THF (50 mL) and H2O (5 mL), then the mixture was stirred at 90 ℃ for 12 h under an N2atmosphere. LCMS showing the desired mass was observed. The reaction was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to produce methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl] amino]pyrimidine-5-carboxylate (3.8 g, 6.43 mmol, 83.35% yield, 96% purity) as a yellow solid.

[1056] MS (ESI) m / z = 568.2 [M+H]+.

[1057] Step c.To a solution of methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]amino]pyrimidine-5-carboxylate (3.8 g, 6.70 mmol) in THF (50 mL) was added LiAlH4(2.5 M, 5.36 mL) at 0 ℃, then the mixture was stirred at 0 ℃ for 1 h under an N2atmosphere. LCMS showing the desired mass was observed. The reaction mixture was quenched by addition of H2O (2 mL) at 25 ℃, then diluted with H2O (50 mL) and extracted with EtOAc (50 mL Х 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]amino]pyrimidin-5-yl]methanol (3.4 g, crude) as yellow solid.

[1058] MS (ESI) m / z = 540.3 [M+H]+.

[1059] Step d.To a solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]amino]pyrimidin-5-yl]methanol (0.5 g, 926.70 μmol) in DCM (2 mL) was added SOCl2(220.50 mg, 1.85 mmol, 134.61 μL), then the mixture was stirred at 25 ℃ for 1 h. LCMS showing the desired mass was observed. The reaction was concentrated under reduced pressure to produce 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrimidin-4-amine (0.6 g, crude) as a yellow solid.

[1060] MS (ESI) m / z = 558.3 [M+H]+.

[1061] Step e.To a solution of 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyrimidin-4-amine (0.5 g, 896.06 μmol) in dioxane (2 mL) and H2O (5 mL) was added Na2SO3(169.41 mg, 1.34 mmol), then the mixture was stirred at 100 ℃ for 2 h. LCMS showing the desired mass was observed. TLC (SiO2, Dichloromethane: Methanol = 10: 1) showing a new spot was observed. The reaction mixture was partitioned between DCM (100 mL) and H2O (100 mL). The organic phase was separated, washed with brine 50 mL, dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Dichloromethane / Methanol gradient @ 40 mL / min) to produce [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (0.2 g, 172.30 μmol, 19.23% yield, 52% purity) as a yellow gum.

[1062] MS (ESI) m / z = 604.2 [M+H]+.

[1063] Step f.A solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (0.2 g, 331.34 μmol) in POCl3(5 mL) and CH3CN (5 mL) was stirred at 60 ℃ for 4 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to remove POCl3(5 mL). The residue was diluted with sat. NaHCO3(20 mL) and extracted with EtOAC (50 mL) (50 mL Х 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The crude product was purified by reversed-phase HPLC(0.1% TFA condition) to produce 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]-3H-isothiazolo[3,4-d]pyrimidine 2,2-dioxide (17.6 mg, 29.83 μmol, 9.00% yield, 99.26% purity, TFA) as a white solid.

[1064] MS (ESI) m / z = 608.1 [M+Na]+;1H NMR (DMSO-d6)δ= 8.61 (s, 1H), 8.57 (s, 1H), 7.93 (s, 1H), 7.68 (d,J= 8.0 Hz, 2H), 7.55 (d,J= 8.0 Hz, 2H), 5.08 (s, 2H), 4.89 (s, 2H), 4.60-4.50 (m, 1H), 3.92 (s, 3H), 1.76-1.71 (m, 1H), 1.47 (d,J= 6.8 Hz, 6H), 1.15-1.10 (m, 2H), 0.89-0.84 (m, 2H).

[1065] Step g.To a solution of 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]-3H-isothiazolo[3,4-d]pyrimidine 2,2-dioxide (45 mg, 76.84 μmol) and 2-bromoethyl(diphenyl)sulfonium;trifluoromethanesulfonate (51.10 mg, 115.27 μmol) in DMF (2 mL) was added TEA (11.66 mg, 115.27 μmol, 16.04 μL), then the mixture was stirred at 25 ℃ for 1 h. LCMS showing the desired mass was observed. The mixture was filtered and the filtrate was directly purified by Prep-HPLC (column: C18 150Х30mm;mobile phase: [water(NH3H2O+NH4HCO3)-ACN];gradient:55%-85% B over 7 min) to produce 6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1'-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl] spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide (10.9 mg, 17.04 μmol, 22.18% yield, 95.62% purity) as a white solid.

[1066] MS (ESI) m / z = 612.2 [M+H]+;1H NMR (DMSO-d6)δ= 8.66 (s, 1H), 8.50 (s, 1H), 8.19 (s, 1H), 7.57 (s, 4H), 5.11 (s, 2H), 4.50-4.37 (m, 1H), 3.83 (s, 3H), 2.11 (d,J= 16.0 Hz, 4H), 1.75-1.71 (m, 1H), 1.40 (d,J= 6.4 Hz, 6H), 1.05-0.96 (m, 2H), 0.83- 0.80 (m, 2H).

[1067]

[1068] Example 2

[1069] 6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1'-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide

[1070]

[1071] Step a.To a solution of methyl 2,4-dichloropyrimidine-5-carboxylate (5.6 g, 27.05 mmol) and DIEA (10.49 g, 81.15 mmol, 14.14 mL) in DMF (100 mL) was added Int 2 (6.90 g, 27.05 mmol) at -78 ℃. The mixture was stirred at 25 ℃ for 16 h under an N2atmosphere. LCMS showing the desired mass was observed. The reaction mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to produce methyl 2-chloro-4-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]amino]pyrimidine-5-carboxylate (3.6 g, 6.82 mmol, 25.22% yield, 80.7% purity) as a yellow solid.

[1072] MS (ESI) m / z = 426.0 [M+H]+;1H NMR (DMSO-d6)δ= 9.06 (t,J= 6.0 Hz, 1H), 8.62 (s, 1H), 7.53 (s, 4H), 6.71 (s, 1H), 4.78 (d,J= 6.4 Hz, 2H), 3.85 (s, 3H), 2.32 (s, 3H).

[1073] Step b.To a solution of methyl 2-chloro-4-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]amino]pyrimidine-5-carboxylate (3.5 g, 8.22 mmol) and (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boronic acid (1.91 g, 9.86 mmol) in dioxane (50 mL) and H2O (5 mL) were added ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (535.73 mg, 822.00 μmol) and K3PO4(5.23 g, 24.66 mmol). The mixture was stirred at 90 ℃ for 16 h under an N2atmosphere. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to produce methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]amino] pyrimidine-5-carboxylate (3.2 g, 4.33 mmol, 52.67% yield, 73% purity) as a yellow solid.

[1074] MS (ESI) m / z = 540.1 [M+H]+.

[1075] Step c.To a solution of methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]amino]pyrimidine-5-carboxylate (3.2 g, 5.93 mmol) in THF (30 mL) was added LiAlH4(2.5 M in THF, 4.75 mL) slowly at 0 ℃. Then, the mixture was stirred at 0 ℃ for 1 h under an N2atmosphere. LCMS showing the desired mass was observed. The reaction mixture was quenched by addition H2O (5 mL) slowly at 25 ℃, and then diluted with NaOH (15% w / w, 5 mL) and H2O (5 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to produce [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]amino]pyrimidin-5-yl]methanol (2.1 g, 3.82 mmol, 64.37% yield, 93% purity) as a yellow solid.

[1076] MS (ESI) m / z = 512.2 [M+H]+.

[1077] Step d.To a solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]amino]pyrimidin-5-yl]methanol (1 g, 1.96 mmol) in DCM (10 mL) was added SOCl2(465.18 mg, 3.91 mmol). The mixture was stirred at 25 ℃ for 1 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-N-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]pyrimidin-4-amine (1 g, crude) as a yellow solid.

[1078] MS (ESI) m / z = 530.2 [M+H]+.

[1079] Step e.To a solution of 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-N-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]pyrimidin-4-amine (1 g, 1.89 mmol) in H2O (10 mL) and dioxane (4 mL) was added Na2SO3(475.68 mg, 3.77 mmol). The mixture was stirred at 100 ℃ for 2 h. LCMS showing the desired mass was observed. The reaction mixture was partitioned between DCM (100 mL) and H2O (100 mL). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Methanol / Dichloromethane gradient @ 40 mL / min) to produce [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (120 mg, 181.39 μmol, 9.61% yield, 87% purity) as a yellow solid.

[1080] MS (ESI) m / z = 576.2 [M+H]+.

[1081] Step f.To a solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (160 mg, 277.99 μmol) in CH3CN (5 mL) was added POCl3(5 mL). The mixture was stirred at 80 ℃ for 16 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The crude product was purified by reversed-phase column (0.1% FA condition) to produce 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3H-isothiazolo[3,4-d]pyrimidine 2,2-dioxide (140 mg, 138.11 μmol, 49.68% yield, 80% purity) as a yellow solid.

[1082] MS (ESI) m / z = 278.2 1 / 2[M+2H]+;1H NMR (DMSO-d6)δ= 8.65 (d,J= 2.4 Hz, 2H), 7.56 (d,J= 4.8 Hz, 4H), 6.75 (s, 1H), 5.10 (s, 2H), 5.02 (s, 2H), 3.82 (s, 3H), 2.32 (s, 3H), 1.79-1.63 (m, 1H), 1.03-0.98 (m, 2H), 0.83 -0.81 (m, 2H).

[1083] Step g.To a solution of 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]-3H-isothiazolo[3,4-d]pyrimidine 2,2-dioxide (110 mg, 197.29 μmol) in DMF (2 mL) were added 2-bromoethyl(diphenyl)sulfonium;trifluoromethanesulfonate (131.19 mg, 295.94 μmol) and TEA (29.95 mg, 295.94 μmol, 41.19 μL). The reaction mixture was stirred at 25 ℃ for 6 h. LCMS showing the desired mass was observed. The reaction was filtered, and to the filtrate was added MeOH (1 mL). The crude product was purified by reversed-phase HPLC(column: Welch Xtimate C18 150*30mm*5um;mobile phase: [water (FA)-ACN]; gradient: 64%-84% B over 7 min) to produce 6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1'-[[4-[5-methyl-3-(trifluoromethyl)pyrazol-1-yl]phenyl]methyl]spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide (15.9 mg, 26.34 μmol, 13.35% yield, 96.69% purity) as a white solid.

[1084] MS (ESI) m / z = 584.2 [M+H]+;1H NMR (DMSO-d6)δ= 8.66 (s, 1H), 8.50 (s, 1H), 7.60-7.55 (m, 4H), 6.77 (s, 1H), 5.12 (s, 2H), 3.83 (s, 3H), 2.33 (s, 3H), 2.13-2.05 (m, 4H), 1.76-1.68 (m, 1H), 1.03-0.96 (m, 2H), 0.85-0.82 (m, 2H).

[1085]

[1086]

[1087] Example 3

[1088] 3-[4-[[6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2',2'-dioxo-spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine]-1'-yl]methyl]phenyl]-1H-pyridazin-6-one

[1089] [Rectified under Rule 91, 30.08.2024]

[1090] Step a.To a mixture of 3-bromo-1H-pyridazin-6-one (20 g, 114.30 mmol) and 1-(chloromethyl)-4-methoxy-benzene (21.48 g, 137.16 mmol) in DMF (200 mL) was added Cs2CO3(74.48 g, 228.59 mmol), then the mixture was stirred at 25 °C for 16 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 3: 1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to produce 6-bromo-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (52 g, 98.67 mmol, 86.33% yield, 56% purity) as a yellow oil.

[1091] MS (ESI) m / z = 295.0 [M+H]+.

[1092] Step b.To a solution of 6-bromo-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (20 g, 67.77 mmol) in dioxane (250 mL) and H2O (25 mL) were added (4-cyanophenyl)boronic acid (11.95 g, 81.32 mmol), cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (4.96 g, 6.78 mmol), K2CO3(18.73 g, 135.53 mmol) under an N2atmosphere, then the mixture was stirred at 90 °C for 16 h under an N2atmosphere. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether : Ethyl acetate = 1: 1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethylacetate / Petroleum ether gradient @ 100 mL / min) to produce 4-[1-[(4-methoxyphenyl)methyl]-6-oxo-pyridazin-3-yl]benzonitrile (14.7 g, 40.25 mmol, 59.40% yield, 86.9% purity) as a yellow solid.

[1093] MS (ESI) m / z = 318.2 [M+H]+.

[1094] Step c.In a flow reactor, to a solution of 4-[1-[(4-methoxyphenyl)methyl]-6-oxo-pyridazin-3-yl]benzonitrile (14.7 g, 46.32 mmol) in THF (200 mL) and NH3 / MeOH (100 mL) were added 14% Co / Al2O3(147 mg), then the mixture was reacted at 120 °C for 10 h under an under an H2. LCMS showing the desired mass was observed. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to produce 6-[4-(aminomethyl)phenyl]-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (15.8 g, crude) as a yellow oil, which was used directly without any further purification.

[1095] MS (ESI) m / z = 321.9 [M+H]+.

[1096] Step d.To a solution of 6-[4-(aminomethyl)phenyl]-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (15.6 g, 48.54 mmol) and methyl 2,4-dichloropyrimidine-5-carboxylate (10.05 g, 48.54 mmol) in THF (500 mL) was added DIEA (18.82 g, 145.63 mmol, 25.36 mL) at -78 °C, then the mixture was warmed to 25 °C and stirred at 25 °C for 16 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethylacetate / Petroleum ether gradient @ 100 mL / min) to produce methyl 2-chloro-4-[[4-[1-[(4-methoxyphenyl)methyl]-6-oxo-pyridazin-3-yl]phenyl]amino]pyrimidine-5-carboxylate (23 g, 39.74 mmol, 81.87% yield, 85% purity) as a yellow solid.

[1097] MS (ESI) m / z = 492.0 [M+H]+.

[1098] Step e.To a solution of methyl 2-chloro-4-[[4-[1-[(4-methoxyphenyl)methyl]-6-oxo-pyridazin-3-yl]phenyl]amino]pyrimidine-5-carboxylate (10 g, 20.33 mmol) in THF (500 mL) and H2O (50 mL) were added (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boronic acid (7.89 g, 40.66 mmol), ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (1.32 g, 2.03 mmol), and K3PO4(12.95 g, 60.98 mmol) under an N2atmosphere, then the mixture was stirred at 90 °C for 16 h under an N2atmosphere. LCMS showing the desired mass was observed. The reaction mixture was directly concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to produce methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-[(4-methoxyphenyl)methyl]-6-oxo-pyridazin-3-yl]phenyl]amino]pyrimidine-5-carboxylate (3.2 g, 3.59 mmol, 17.67% yield, 68% purity) as a yellow solid.

[1099] MS (ESI) m / z = 606.2 [M+H]+.

[1100] Step f.To a solution of methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-[(4-methoxyphenyl)methyl]-6-oxo-pyridazin-3-yl]phenyl]amino]pyrimidine-5-carboxylate (3.2 g, 5.28 mmol) and CaCl2(1.76 g, 15.85 mmol) in THF (20 mL) and H2O (5 mL) was added NaBH4(599.68 mg, 15.85 mmol) at 0 °C under an N2atmosphere, then the temperature of the reaction mixture was allowed to warm to 25 °C and then the reaction mixture was stirred at 25 °C for 2 h. LCMS showing the desired mass was observed. TLC (SiO2, Dichloromethane: Methanol = 10: 1) showing a new spot was observed. The reaction mixture was quenched by addition of H2O (50 mL) at 25 °C and extracted with Ethyl acetate (50 mL Х 3). The combined organic layers were washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~10% Methanol / Dichloromethane gradient @ 50 mL / min) to produce 6-[4-[[[2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-5-(hydroxymethyl)pyrimidin-4-yl]amino]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (0.3 g, 506.38 μmol, 9.58% yield, 97.5% purity) as a yellow solid.

[1101] MS (ESI) m / z = 578.3 [M+H]+;1H NMR (DMSO-d6)δ= 8.59 (s, 1H), 8.18 (s, 1H), 8.01 (d,J= 9.6 Hz, 1H), 7.80 (d,J= 8.4 Hz, 2H), 7.51 (t,J= 5.6 Hz, 1H), 7.40 (d,J= 8.4 Hz, 2H), 7.33 (d,J= 8.8 Hz, 2H), 7.06 (d,J= 9.6 Hz, 1H), 6.90 (d,J= 8.8 Hz, 2H), 5.31 (t,J= 5.6 Hz, 1H), 5.24 (s, 2H), 4.62 (d,J= 5.6 Hz, 2H), 4.50 (d,J= 5.6 Hz, 2H), 3.78 (s, 3H), 3.72 (s, 3H), 1.63-1.56 (m, 1H), 0.96-0.90 (m, 2H), 0.78-0.70 (m, 2H).

[1102] Step g.To a solution of 6-[4-[[[2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-5-(hydroxymethyl)pyrimidin-4-yl]amino]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (0.3 g, 519.36 μmol) in DCM (5 mL) was added SOCl2(123.58 mg, 1.04 mmol, 75.44 μL), then the mixture was stirred at 25 °C for 2 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce 6-[4-[[[5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)pyrimidin-4-yl]amino]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (0.3 g, crude) as a yellow solid.

[1103] MS (ESI) m / z = 619.8 [M+Na+2]+.

[1104] Step h.To a solution of 6-[4-[[[5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)pyrimidin-4-yl]amino]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]pyridazin-3-one (0.3 g, crude) in dioxane (4 mL) and H2O (6 mL) was added disodium;sulfite (126.87 mg, 1.01 mmol), then the mixture was stirred at 100 °C for 2 h. LCMS showing the desired mass was observed. TLC (SiO2, Dichloromethane: Methanol = 10: 1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to produce [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-[(4-methoxyphenyl)methyl]-6-oxo-pyridazin-3-yl]phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (compound 9, 260 mg, 206.64 μmol, 41.06% yield, 58% purity) as a yellow solid.

[1105] MS (ESI) m / z = 642.2 [M+H]+.

[1106] Step i.A solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-[(4-methoxyphenyl)methyl]-6-oxo-pyridazin-3-yl]phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (110 mg, 171.42 μmol) in CH3CN (5 mL) and POCl3(5 mL) was stirred at 80 °C for 2 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to remove POCl3. The residue was diluted with NaHCO3(50 mL) and extracted with EtOAc (50 mL Х 3). The combined organic layers were washed with brine (30 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was further purified by Prep-HPLC (column: Phenomenex Gemini-NX 150*30mm*5um;mobile phase: [water(0.05%HCl)-ACN];B%: 65%-95%) to produce 1-[[4-(6-chloropyridazin-3-yl)phenyl]methyl]-6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3H-isothiazolo[3,4-d]pyrimidine 2,2-dioxide (25 mg, 31.84 μmol, 18.57% yield, 81% purity, TFA) as a yellow solid.

[1107] MS (ESI) m / z = 522.0 [M+H]+.

[1108] Step j.To a solution of 1-[[4-(6-chloropyridazin-3-yl)phenyl]methyl]-6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3H-isothiazolo[3,4-d]pyrimidine 2,2-dioxide (25 mg, 47.89 μmol, TFA) in DMF (5 mL) were added 2-bromoethyl(diphenyl)sulfonium;trifluoromethanesulfonate (42.46 mg, 95.79 μmol) and TEA (14.54 mg, 143.68 μmol, 20.00 μL), then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) showing the desired mass was observed. The reaction mixture was partitioned between EtOAC (50 mL) and H2O (50 mL). The organic phase was separated, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 4 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 30 mL / min) to produce 1'-[[4-(6-chloropyridazin-3-yl)phenyl]methyl]-6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide (25 mg, 31.48 μmol, 65.72% yield, 69% purity) as a yellow solid.

[1109] MS (ESI) m / z = 548.1 [M+H]+.

[1110] Step k.To a solution of 1'-[[4-(6-chloropyridazin-3-yl)phenyl]methyl]-6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide (20 mg, 36.50 μmol) in acetic acid (4 mL) was added NaOAc (5.99 mg, 72.99 μmol), then the mixture was stirred at 100 °C for 2 h. LCMS showing the desired mass was observed. The mixture was purified directly without any work-up. The residue was purified by reversed phase column (column: 40 g C18 reversed phase column; mobile phase: [Water (0.05%TFA)-ACN];B%: 0%-60%, 30min) to produce 3-[4-[[6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2',2'-dioxo-spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine]-1'-yl]methyl]phenyl]-1H-pyridazin-6-one (5.15 mg, 7.54 μmol, 20.65% yield, 94.17% purity, TFA) as a white solid.

[1111] MS (ESI) m / z = 530.1 [M+H]+;1H NMR (CD3OD)δ= 8.59 (s, 1H), 8.31 (s, 1H), 8.05 (d,J= 9.6 Hz, 1H), 7.87 (d,J= 8.4 Hz, 2H), 7.61 (d,J= 8.4 Hz, 2H), 7.08 (d,J= 9.6 Hz, 1H), 5.10 (s, 2H), 3.90 (s, 3H), 2.23-2.18 (m, 2H), 1.98-1.95 (m, 2H), 1.69-1.65 (m, 1H), 1.11-1.06 (m, 2H), 0.87-0.82 (m, 2H).

[1112] Example 4

[1113] 6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1'-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]methyl]spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide

[1114]

[1115] Step a.To a solution of 4-methoxycarbonylbicyclo[2.2.2]octane-1-carboxylic acid (8.45 g, 39.81 mmol) in THF (120 mL) was added BH3THF (1 M in THF, 63.70 mL) dropwise at 0 °C under an N2atmosphere. The mixture was stirred at 25 °C for 12 h under an N2atmosphere. TLC (Petroleum ether: Ethyl acetate = 3:1) indicated the starting material was consumed completely and one major new spot was detected. The reaction mixture was quenched by addition 2M HCl (200 mL) slowly at 0 °C under an N2atmosphere, and the mixture was stirred at 25 °C for 1 h. Then the mixture was diluted with H2O (100 mL) and extracted with EtOAc (150 mL Х 3). The combined organic layers were washed with brine (150 mL Х 3), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce methyl 4-(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylate (7.39 g, crude) as a colorless oil.

[1116] 1H NMR (DMSO-d6) = 4.36 (t,J= 5.2 Hz, 1H), 3.55 (s, 3H), 3.03 (d,J= 5.2 Hz, 2H), 1.69-1.63 (m, 6H), 1.36-1.31 (m, 6H).

[1117] Step b.To a solution of methyl 4-(hydroxymethyl)bicyclo[2.2.2]octane-1-carboxylate (7.39 g, crude) in DCM (100 mL) was added DMP (20.55 g, 48.46 mmol) slowly at 0 °C. The mixture was stirred at 25 °C for 1 h under an N2atmosphere. TLC (Petroleum ether: Ethyl acetate = 3:1) indicated the starting material was consumed completely and one major new spot was detected. The reaction mixture was filtered. The filtrate was washed with saturated aq. NaHCO3(150 mL Х 3) and saturated aq. (150 mL Х 3). The combined organic layers were washed with brine (150 mL Х 2), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to produce methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate (12.05 g, crude) as a light yellow solid.

[1118] 1H NMR (DMSO-d6) = 9.41 (s, 1H), 3.58 (s, 3H), 1.75-1.71 (m, 6H), 1.61-1.56 (m, 6H).

[1119] Step c.To a mixture of 3,3-dibromo-1,1,1-trifluoro-propan-2-one (21.54 g, 79.82 mmol) in H2O (48.2 mL) was added NaOAc (10.07 g, 122.81 mmol). The mixture was stirred at 100 °C under an N2atmosphere for 1 h. The mixture was cooled to 0 °C, and to the mixture, a mixture of methyl 4-formylbicyclo[2.2.2]octane-1-carboxylate (12.05 g, crude) and NH3H2O (74.63 g, 596.23 mmol, 82.01 mL, 28% purity) in MeOH (126 mL) was added slowly at 0 °C. The mixture was stirred at 25 °C under an N2atmosphere for 12 h. LCMS showing the desired mass was detected. The mixture was cooled to 25 °C, then the mixture was poured into ice water (800 mL) slowly. The mixture was stirred at 25 °C for 0.5 h. The mixture was filtered and the filter cake was washed with water (500 mL Х 3). The filter cake was concentrated and dried under reduced pressure to produce methyl 4-[4-(trifluoromethyl)-1H-imidazol-2-yl]bicyclo[2.2.2]octane-1-carboxylate (6.39 g, 20.08 mmol, 32.70% yield, 95% purity) as a light brown solid.

[1120] MS (ESI) m / z = 303.0 [M+H]+;1H NMR (DMSO-d6) = 12.29 (br s, 1H), 7.63 (s, 1H), 3.59 (s, 3H), 1.86-1.76 (m, 12H).

[1121] Step d.To a solution of methyl 4-[4-(trifluoromethyl)-1H-imidazol-2-yl]bicyclo[2.2.2]octane-1-carboxylate (6.86 g, 22.69 mmol) in DMF (90 mL) were added 2-iodopropane (15.43 g, 90.77 mmol, 9.06 mL) and Cs2CO3(22.18 g, 68.08 mmol). The mixture was stirred at 90 °C for 12 h under an N2atmosphere. LCMS showing the desired mass was detected and about a half of methyl 4-[4-(trifluoromethyl)-1H-imidazol-2-yl]bicyclo[2.2.2]octane-1-carboxylate remained. To the mixture was added 2-iodopropane (15.43 g, 90.77 mmol, 9.06 mL) and then the mixture was stirred at 90 °C for 12 h under an N2atmosphere. LCMS showing the desired mass was detected. The mixture was poured into ice water (200 mL) and a solid was formed. The mixture was filtered and the filter cake was washed with water (150 mL Х 3). The filter cake was concentrated and dried under reduced pressure to produce a residue. The residue was purified by flash silica gel column chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~3% MeOH / DCM gradient @ 40 mL / min) to produce methyl 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]bicyclo[2.2.2]octane-1-carboxylate (3.59 g, 10.01 mmol, 44.10% yield, 96% purity) as a brown solid.

[1122] MS (ESI) m / z = 345.2 [M+H]+.

[1123] Step e.To a solution of methyl 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]bicyclo[2.2.2]octane-1-carboxylate (6.26 g, 18.18 mmol) in MeOH (40 mL) and THF (40 mL) was added a solution of LiOHH2O (3.05 g, 72.71 mmol) in H2O (20 mL). The mixture was stirred at 25 °C for 12 h under an N2atmosphere. LCMS showing the desired mass was detected. The reaction mixture was poured into ice water (100 mL). The pH of the mixture was adjusted to about ~2 with 2M HCl (~45 mL). A light yellow solid was obtained and the solid was filtered and concentrated under reduced pressure to produce 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]bicyclo[2.2.2]octane-1-carboxylic acid (4.4 g, 12.52 mmol, 68.88% yield, 94% purity) as a light yellow solid.

[1124] MS (ESI) m / z = 331.1 [M+H]+;1H NMR (DMSO-d6) = 12.08 (br s, 1H), 7.94 (d,J= 1.2 Hz, 1H), 4.91-4.81 (m, 1H), 1.96-1.90 (m, 6H), 1.83-1.74 (m, 6H), 1.37 (d,J= 6.4 Hz, 6H).

[1125] Step f.To a solution of 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]bicyclo[2.2.2]octane-1-carboxylic acid (4.4 g, 13.32 mmol) in DMF (25 mL) were added NH4Cl (1.07 g, 19.98 mmol), TEA (4.04 g, 39.96 mmol, 5.56 mL) and BOP (6.48 g, 14.65 mmol). The mixture was stirred at 25 °C for 2 h under an N2atmosphere. LCMS showing the desired mass was detected and an intermediate state was detected. TEA (4.04 g, 39.96 mmol, 5.56 mL) and NH4Cl (1.07 g, 19.98 mmol) were added to the reaction mixture. The mixture was stirred at 25 °C for 12 h under an N2atmosphere. LCMS showing the desired mass was detected. The mixture was concentrated under reduced pressure to produce a residue. The mixture was purified with reversed-phase HPLC (Eluent of 0~45% MeCN in H2O (contained 0.075% NH3H2O) gradient) to produce 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]bicyclo[2.2.2]octane-1-carboxamide (3.81 g, 10.41 mmol, 78.16% yield, 86% purity) as a white solid.

[1126] MS (ESI) m / z = 330.1 [M+H]+;1H NMR (DMSO-d6) = 7.93 (d,J= 1.2 Hz, 1H), 6.96 (br s, 1H), 6.73 (br s, 1H), 4.86-4.79 (m, 1H), 1.93-1.88 (m, 6H), 1.77-1.72 (m, 6H), 1.37 (d,J= 6.8 Hz, 6H).

[1127] Step g.To a solution of 4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]bicyclo[2.2.2]octane-1-carboxamide (3.81 g, 11.57 mmol) in THF (60 mL) was added BH3-Me2S (10 M, 5.78 mL) dropwise at 0 °C. The mixture was stirred at 70 °C for 1.5 h under an N2atmosphere. LCMS showing the desired mass was detected. The reaction mixture was quenched by addition of MeOH (50 mL) slowly at 0 °C. Then the mixture was stirred at 25 °C for 0.5 h. Then the mixture was stirred at 50 °C for 0.5 h. Then the mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel column chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~10% MeOH / DCM gradient @ 40 mL / min) to produce [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]methanamine (1.68 g, 4.79 mmol, 41.44% yield, 90% purity) as a white solid.

[1128] MS (ESI) m / z = 315.9 [M+H]+.

[1129] Step h.To a solution of methyl 2,4-dichloropyrimidine-5-carboxylate (1.43 g, 6.89 mmol) in THF (30 mL) were added DIEA (1.48 g, 11.48 mmol, 2.00 mL) and [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]methanamine (1.81 g, 5.74 mmol) at -78 °C. The mixture was stirred at -78 °C for 2 h under an N2atmosphere. LCMS showing the desired mass was detected. The mixture was diluted with H2O (60 mL) and extracted with EtOAc (80 mL Х 3). The combined organic layers were washed with brine (60 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by flash silica gel column chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~40% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to produce methyl 2-chloro-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]amino]pyrimidine-5-carboxylate (1.49 g, 2.55 mmol, 44.34% yield, 84% purity) as a white solid.

[1130] MS (ESI) m / z = 486.1 [M+H]+;1H NMR (DMSO-d6) = 8.63 (s, 1H), 8.50 (t,J= 5.6 Hz, 1H), 7.92 (d,J= 0.8 Hz, 1H), 4.91-4.81 (m, 1H), 3.87 (s, 3H), 1.95-1.88 (m, 6H), 1.55-1.48 (m, 6H), 1.36 (d,J= 6.4 Hz, 6H).

[1131] Step i.To a solution of methyl 2-chloro-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]amino]pyrimidine-5-carboxylate (500 mg, 1.03 mmol) and (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boronic acid (399.23 mg, 2.06 mmol) in THF (10 mL) and H2O (1 mL) were added K3PO4(436.83 mg, 2.06 mmol) and ditert-butyl(cyclopenta-1,4-dien-1-yl)phosphane;dichloropalladium;iron (67.06 mg, 102.90 μmol), then the mixture was stirred at 100 °C for 8 h under an N2atmosphere. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to produce methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]amino]pyrimidine-5-carboxylate (0.53 g, 875.02 μmol, 85.04% yield, 99% purity) as a yellow solid.

[1132] MS (ESI) m / z = 600.2 [M+H]+.

[1133] Step j.To a solution of methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]amino]pyrimidine-5-carboxylate (0.5 g, 833.83 μmol) in THF (10 mL) was added LiAlH4(2.5 M, 667.06 μL) dropwise over 0.5 min at 0 °C, then the mixture was stirred at 0 °C for 1 h under an N2atmosphere. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 0:1) showing a new spot was observed. The reaction mixture was quenched by addition H2O (1 mL) at 0 °C, and then diluted with aq. NaOH (1 mL, 15%) and H2O (1 mL). Then after quenching, Na2SO4was added, and the mixture was filtered. The filtrate was concentrated in vacuo to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100%Ethylacetate / Petroleum ether gradient @ 40 mL / min) to produce [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]amino]pyrimidin-5-yl]methanol (0.35 g, 602.48 μmol, 72.26% yield, 98.4% purity) as a yellow solid.

[1134] MS (ESI) m / z = 572.2 [M+H]+.

[1135] Step k.To a solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]amino]pyrimidin-5-yl]methanol (0.35 g, 612.28 μmol) in DCM (5 mL) was added SOCl2(145.69 mg, 1.22 mmol, 88.94 μL), then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]methyl]pyrimidin-4-amine (0.35 g, crude) as a yellow solid.

[1136] MS (ESI) m / z = 590.1 [M+H]+.

[1137] Step l.To a solution of 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]methyl]pyrimidin-4-amine (0.35 g, crude) in dioxane (2 mL) and H2O (3 mL) was added disodium;sulfite (149.52 mg, 1.19 mmol), then the mixture was stirred at 100 °C for 2 h. LCMS showing the desired mass was observed. TLC (SiO2, Dichloromethane: Methanol = 10: 1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Methanol: Dichloromethane gradient @ 40 mL / min) to produce [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]amino]pyrimidin-5-yl]methanesulfonic acid (0.22 g, 200.72 μmol, 33.84% yield, 58% purity) as a yellow solid.

[1138] MS (ESI) m / z = 636.3 [M+H]+.

[1139] Step m.A mixture of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]amino]pyrimidin-5-yl]methanesulfonic acid (190 mg, 298.88 μmol) in CH3CN (5 mL) was added POCl3(458.28 mg, 2.99 mmol, 278.59 μL), then the mixture was stirred at 80 °C for 2 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to remove POCl3. The residue was diluted with NaHCO3(50 mL) and extracted with EtOAc (50 mL Х 3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The crude product was purified by reversed-phase HPLC (0.1% FA condition) to produce 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]methyl]-3H-isothiazolo[3,4-d]pyrimidine 2,2-dioxide (12.5 mg, 15.78 μmol, 5.28% yield, 78% purity) as a yellow solid.

[1140] MS (ESI) m / z = 618.2 [M+H]+.

[1141] Step n.To a solution of 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]methyl]-3H-isothiazolo[3,4-d]pyrimidine 2,2-dioxide (20 mg, 32.38 μmol) in DMF (5 mL) were added 2-bromoethyl(diphenyl)sulfonium;trifluoromethanesulfonate (21.53 mg, 48.57 μmol) and TEA (9.83 mg, 97.14 μmol, 13.52 μL), then the mixture was stirred at 25 °C for 2 h. LCMS showing the desired mass was observed. The reaction mixture was purified directly without any work-up. The reaction mixture was purified by reversed-phase HPLC (40 g C18 reversed phase column, mobile phase: [water(0.05% TFA)-ACN]; B%: 0%-80%, 30 min) ) to produce 6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1'-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-1-bicyclo[2.2.2]octanyl]methyl]spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide (2.78 mg, 4.24 μmol, 13.09% yield, 98.15% purity, TFA) as a white solid.

[1142] MS (ESI) m / z = 644.2 [M+H]+;1H NMR (CD3OD) = 8.63 (s, 1H), 8.31 (s, 1H), 7.85 (s, 1H), 5.03-4.99 (m, 1H), 3.96 (s, 3H), 3.69 (s, 2H), 2.19-2.13 (m, 2H), 2.10-2.03 (m, 6H), 1.97-1.92 (m, 2H), 1.81-1.76 (m, 6H), 1.48 (d,J= 6.4 Hz, 6H), 1.35-1.31 (m, 1H), 1.19 (dd,J= 4.4, 3.2 Hz, 2H), 0.99 (dd,J= 8.0, 3.2 Hz, 2H).

[1143]

[1144] Example 5

[1145] 4-[4-[[6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2',2'-dioxo-spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine]-1'-yl]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]phthalazin-1-one

[1146] [Rectified under Rule 91, 30.08.2024]

[1147] Step a.To a mixture of 4-bromo-2H-phthalazin-1-one (10 g, 44.44 mmol) and 1-(chloromethyl)-4-methoxy-benzene (13.92 g, 88.87 mmol, 12.06 mL) in DMF (500 mL) was added Cs2CO3(28.96 g, 88.87 mmol), then the mixture was stirred at 25 °C for 1 h under an N2atmosphere. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 0: 1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 100 mL / min) to produce 4-bromo-2-[(4-methoxyphenyl)methyl]phthalazin-1-one (28.3 g, crude) as a yellow solid.

[1148] MS (ESI) m / z = 344.8 [M+H]+.

[1149] Step b.To a solution of 4-bromo-2-[(4-methoxyphenyl)methyl]phthalazin-1-one (27.3 g, 79.09 mmol) in H2O (100 mL) and dioxane (1000 mL) were added (4-cyanophenyl)boronic acid (23.24 g, 158.17 mmol), cyclopentyl(diphenyl)phosphane;dichloropalladium;iron (5.79 g, 7.91 mmol), and K2CO3(21.86 g, 158.17 mmol), then the mixture was stirred at 90 °C for 16 h under an N2atmosphere. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 330 g SepaFlash® Silica Flash Column, Eluent of 0~100%Ethylacetate / Petroleum ether gradient @ 100 mL / min) to produce 4-[3-[(4-methoxyphenyl)methyl]-4-oxo-phthalazin-1-yl]benzonitrile (40 g, 62.06 mmol, 78.47% yield, 57% purity) as a yellow solid.

[1150] MS (ESI) m / z = 368.1 [M+H]+.

[1151] Step c.4-[3-[(4-methoxyphenyl)methyl]-4-oxo-phthalazin-1-yl]benzonitrile (40 g, 108.87 mmol) was dissolved in NH3 / MeOH (300 mL) and THF (300 mL). The mixture was stirred at 120 °C under an H2atmosphere. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce residue. The crude product was used directly without any further purification to produce 4-[4-(aminomethyl)phenyl]-2-[(4-methoxyphenyl)methyl]phthalazin-1-one (35.6 g, crude) as a yellow solid.

[1152] MS (ESI) m / z = 372.0 [M+H]+.

[1153] Step d.To a solution of methyl 2,4-dichloropyrimidine-5-carboxylate (4.5 g, 21.74 mmol) and 4-[4-(aminomethyl)phenyl]-2-[(4-methoxyphenyl)methyl]phthalazin-1-one (8.07 g, 21.74 mmol) in THF (500 mL) was added DIEA (8.43 g, 65.21 mmol, 11.36 mL) at -78 °C, then the mixture was warmed to 25 °C and stirred at 25 °C for 16 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 60 mL / min) to produce methyl 2-chloro-4-[[4-[3-[(4-methoxyphenyl)methyl]-4-oxo-phthalazin-1-yl]phenyl]amino]pyrimidine-5-carboxylate (1.8 g, 2.82 mmol, 12.99% yield, 85% purity) as a yellow solid.

[1154] MS (ESI) m / z = 542.1 [M+H]+.

[1155] Step e.To a mixture of methyl 2-chloro-4-[[4-[3-[(4-methoxyphenyl)methyl]-4-oxo-phthalazin-1-yl]phenyl]amino]pyrimidine-5-carboxylate (1.5 g, 2.77 mmol) and (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boronic acid (644.28 mg, 3.32 mmol) in THF (50 mL) and H2O (5 mL) were added ditert-butyl(cyclopentyl)phosphane;dichloropalladium;iron (180.38 mg, 276.76 μmol) and K3PO4(1.76 g, 8.30 mmol) under an N2atmosphere, then the mixture was stirred at 90 °C for 4 h under an N2atmosphere. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 50 mL / min) to produce methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[3-[(4-methoxyphenyl)methyl]-4-oxo-phthalazin-1-yl]phenyl]amino]pyrimidine-5-carboxylate (1.1 g, 973.01 μmol, 35.16% yield, 58% purity) as a yellow solid.

[1156] MS (ESI) m / z = 656.2 [M+H]+.

[1157] Step f.To a solution of methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[3-[(4-methoxyphenyl)methyl]-4-oxo-phthalazin-1-yl]phenyl]amino]pyrimidine-5-carboxylate (0.9 g, 1.37 mmol) in THF (10 mL) was added LiAlH4(2.5 M in THF, 1.10 mL) dropwise at 0 °C under an N2atmosphere, and the reaction mixture was stirred at 0 °C for 1 h under an N2atmosphere. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 0: 1) showing a new spot was observed. The reaction mixture was quenched by addition H2O (10 mL) at 0 °C, and then diluted with NaOH (10 mL, 15%) and H2O (10 mL). Then, Na2SO4was added, and the mixture was filtered. The filtrate was concentrated in vacuo to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100%Ethylacetate / Petroleum ether gradient @ 40 mL / min) to produce 4-[4-[[[2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-5-(hydroxymethyl)pyrimidin-4-yl]amino]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]phthalazin-1-one (300 mg, 339.34 μmol, 24.72% yield, 71% purity) as a yellow solid.

[1158] MS (ESI) m / z = 628.2 [M+H]+;1H NMR (DMSO-d6) = 8.60 (s, 1H), 8.42-8.33 (m, 1H), 8.24-8.16 (m, 1H), 7.92-7.88 (m, 1H), 7.71-7.66 (m, 1H), 7.54-7.43 (m, 4H), 7.41-7.25 (m, 4H), 6.92-6.86 (m, 2H), 5.36-5.29 (m, 2H), 4.73-4.63 (m, 2H), 4.55-4.48 (m, 2H), 3.79 (s, 3H), 3.75-3.69 (m, 3H), 1.72-1.57 (m, 1H), 0.96-0.88 (m, 2H), 0.75 (br dd,J= 8.0, 3.2 Hz, 2H).

[1159] Step g.To a solution of 4-[4-[[[2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-5-(hydroxymethyl)pyrimidin-4-yl]amino]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]phthalazin-1-one (0.3 g, 477.94 μmol) in DCM (5 mL) was added SOCl2(113.72 mg, 955.89 μmol, 69.43 μL), then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. The reaction was concentrated under reduced pressure to produce 4-[4-[[[5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)pyrimidin-4-yl]amino]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]phthalazin-1-one (0.3 g, crude) as a yellow solid.

[1160] MS (ESI) m / z = 646.2 [M+H]+.

[1161] Step h.To a solution of 4-[4-[[[5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)pyrimidin-4-yl]amino]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]phthalazin-1-one (300 mg, crude) in H2O (3 mL) and dioxane (2 mL) was added disodium;sulfite (117.04 mg, 928.60 μmol), then the mixture was stirred at 100 °C for 2 h. LCMS showing the desired mass was observed. TLC (SiO2, Dichloromethane: Methanol = 10: 1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Methanol: Dichloromethane gradient @ 40 mL / min) to produce [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[3-[(4-methoxyphenyl)methyl]-4-oxo-phthalazin-1-yl]phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (200 mg, 104.08 μmol, 22.42% yield, 36% purity) as a yellow solid.

[1162] MS (ESI) m / z = 692.2 [M+H]+.

[1163] Step i.A mixture of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[3-[(4-methoxyphenyl)methyl]-4-oxo-phthalazin-1-yl]phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (100 mg, 144.56 μmol) in POCl3(5 mL) and CH3CN (5 mL) was stirred at 80 °C for 2 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to remove POCl3(5 mL). The residue was diluted with NaHCO3(50 mL) and extracted with EtOAc (50mL Х 3). The combined organic layers were washed with brine (10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by reversed phase column (column: 40 g C18 reversed phase column; mobile phase: [Water (0.05%TFA)-ACN];B%: 0%-60%,30min) to produce 4-[4-[[6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2,2-dioxo-3H-isothiazolo[3,4-d]pyrimidin-1-yl]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]phthalazin-1-one (25 mg, 33.77 μmol, 23.36% yield, 91% purity) as a white solid.

[1164] MS (ESI) m / z = 674.2 [M+H]+;1H NMR (DMSO-d6) = 8.66 (d,J= 4.2 Hz, 2H), 8.38 (dd,J= 5.6, 3.6 Hz, 1H), 7.98-7.84 (m, 2H), 7.67 (dd,J= 5.2, 3.2 Hz, 1H), 7.58 (s, 4H), 7.34 (d,J= 8.4 Hz, 2H), 6.88 (d,J= 8.4 Hz, 2H), 5.30 (s, 2H), 5.12 (s, 2H), 5.04 (s, 2H), 3.82 (s, 3H), 3.71 (s, 3H), 1.70 (dd,J= 8.4, 4.4 Hz, 1H), 1.05-0.99 (m, 2H), 0.88-0.84 (m, 2H).

[1165] Step j.To a solution of 4-[4-[[6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2,2-dioxo-3H-isothiazolo[3,4-d]pyrimidin-1-yl]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]phthalazin-1-one (20 mg, 29.69 μmol) in DMF (4 mL) were added TEA (9.01 mg, 89.06 μmol, 12.40 μL) and 2-bromoethyl(diphenyl)sulfonium;trifluoromethanesulfonate (39.48 mg, 89.06 μmol), then the mixture was stirred at 25 °C for 2 h. LCMS showing the desired mass was observed. The reaction mixture was purified directly without any work-up. The reaction mixture was purified by reversed phase column (column: 40 g C18 reversed phase column; mobile phase: [Water (0.05%TFA)-ACN];B%: 0%-60%,30min) to produce 4-[4-[[6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2',2'-dioxo-spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine]-1'-yl]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]phthalazin-1-one (20 mg, 21.15 μmol, 71.25% yield, 74% purity) as a white solid.

[1166] MS (ESI) m / z = 700.2 [M+H]+;1H NMR (DMSO-d6) = 8.66 (s, 1H), 8.50 (s, 1H), 8.43-8.29 (m, 1H), 7.95-7.86 (m, 2H), 7.73-7.63 (m, 1H), 7.59 (s, 4H), 7.38-7.36 (m, 2H), 6.88 (d,J= 8.4 Hz, 2H), 5.30 (s, 2H), 5.13 (s, 2H), 3.82 (s, 3H), 3.71 (s, 3H), 2.16-2.01 (m, 4H), 1.75-170 (m, 1H), 1.05-0.99 (m, 2H), 0.88-0.82 (m, 2H).

[1167] Step k.A solution of 4-[4-[[6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2',2'-dioxo-spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine]-1'-yl]methyl]phenyl]-2-[(4-methoxyphenyl)methyl]phthalazin-1-one (15 mg, 21.44 μmol) in TFA (5 mL) was stirred at 60 °C for 16 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by Prep-HPLC (column: Phenomenex Gemini-NX 150*30mm*5um; mobile phase: [water(0.05%TFA)-ACN];B%: 65%-95%,7min) to produce 4-[4-[[6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-2',2'-dioxo-spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine]-1'-yl]methyl]phenyl]-2H-phthalazin-1-one (1.19 mg, 1.90 μmol, 8.85% yield, 92.41% purity, TFA) as a yellow solid.

[1168] MS (ESI) m / z = 580.3 [M+H]+;1H NMR (DMSO-d6) = 12.87 (s, 1H), 8.66 (s, 1H), 8.50 (s, 1H), 8.41-8.28 (m, 1H), 7.97-7.83 (m, 2H), 7.70-7.63 (m, 1H), 7.59 (s, 4H), 5.13 (s, 2H), 3.83 (s, 3H), 2.11 (br dd,J= 16.0, 3.2 Hz, 4H), 1.75-170 (m, 1H), 1.05-0.98 (m, 2H), 0.88-0.80 (m, 2H).

[1169]

[1170] Example 6

[1171] 6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-7'-fluoro-1'-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]spiro[cyclopropane-1,3'-isothiazolo[4,3-c]pyridine] 2',2'-dioxide

[1172]

[1173] Step a.To a mixture of 2-chloro-3-fluoro-pyridin-4-amine (5.65 g, 38.55 mmol) and (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boronic acid (8.98 g, 46.26 mmol) in dioxane (100 mL) and H2O (10 mL) were added K3PO4(16.37 g, 77.11 mmol), X-Phos Pd G3(1.63 g, 1.93 mmol) and XPhos (1.84 g, 3.86 mmol), the reaction mixture was degassed and purged with N23 times, then stirred at 100 °C for 12 h under an N2atmosphere. The reaction mixture was diluted with water (500 mL), then extracted with EtOAc (600 mL Х 3). The combined organic phases were washed with brine (200 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 65 mL / min) to produce 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-pyridin-4-amine (8.65 g, 20.94 mmol, 54.31% yield, 63% purity) as a light yellow solid.

[1174] MS (ESI) m / z = 260.9 [M+H]+.

[1175] Step b.To a solution of 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-pyridin-4-amine (8.65 g, 33.24 mmol) in CH3CN (100 mL) was added NBS (6.21 g, 34.90 mmol), then the reaction mixture was stirred at 25 °C for 12 h under an N2atmosphere. LCMS showing the desired product was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~35% Ethyl acetate / Petroleum ether gradient @ 65 mL / min) to produce 5-bromo-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-pyridin-4-amine (11.2 g, 32.56 mmol, 97.97% yield, 98.6% purity) as a light yellow solid.

[1176] MS (ESI) m / z = 339.0 [M+H]+;1H NMR (DMSO-d6)δ= 8.68 (s, 1H), 8.26 (s, 1H), 6.66 (s, 2H), 3.89 (s, 3H), 1.76-1.70 (m, 1H), 1.09-1.05 (m, 1H), 1.01-0.94 (m, 1H), 0.93-0.91 (m, 2H).

[1177] Step c.To a solution of 5-bromo-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-pyridin-4-amine (2 g, 5.90 mmol) in DCM (20 mL) were added DMAP (72.04 mg, 589.69 μmol), TEA (1.79 g, 17.69 mmol, 2.46 mL) and Boc2O (5.15 g, 23.59 mmol, 5.42 mL). The mixture was stirred at 25 °C for 2 h. LCMS showing the desired mass was detected. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (100 mL Х 3). The combined organic layers were washed with brine (80 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce tert-butyl N-[5-bromo-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-4-pyridyl]-N-tert-butoxycarbonyl-carbamate (3.5 g, crude) as a yellow solid.

[1178] MS (ESI) m / z = 541.0 [M+H+2]+.

[1179] Step d.To a solution of tert-butyl N-[5-bromo-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-4-pyridyl]-N-tert-butoxycarbonyl-carbamate (3.5 g, crude) in MeOH (50 mL) was added K2CO3(2.69 g, 19.47 mmol). The mixture was stirred at 60 °C for 2 h. LCMS showing the desired mass was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (Petroleum ether : Ethyl acetate= 3 : 1) to produce tert-butyl N-[5-bromo-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-4-pyridyl]carbamate (2.4 g, 5.35 mmol, 82.52% yield, 98% purity) as a white solid.

[1180] MS (ESI) m / z = 438.9 [M+H]+.

[1181] Step e.To a solution of tert-butyl N-[5-bromo-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-4-pyridyl]carbamate (2 g, 4.55 mmol) in DMF (30 mL) were added Int 1 (1.65 g, 5.46 mmol) and Cs2CO3(4.45 g, 13.66 mmol). The mixture was stirred at 25 °C for 2 h. LCMS showing the desired mass was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether @ 50 mL / min) to produce tert-butyl N-[5-bromo-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-4-pyridyl]-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]carbamate (3.5 g, 4.32 mmol, 94.79% yield, 87% purity) as a yellow oil.

[1182] MS (ESI) m / z = 707.1 [M+H+2]+.

[1183] Step f.To a solution of tert-butyl N-[5-bromo-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-4-pyridyl]-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]carbamate (9.90 g, 14.04 mmol) in DMF (50 mL) were added Pd(OAc)2(315.12 mg, 1.40 mmol), DPPF (1.56 g, 2.81 mmol), Et3N (7.10 g, 70.18 mmol, 9.77 mL) and MeOH (50 mL). The suspension was degassed and purged with Ar 3 times. Then the mixture was degassed and purged with CO 3 times. The mixture was stirred under CO (50 psi) at 80 °C for 12 h. LCMS showing the desired product was detected. The reaction mixture was diluted with H2O (100 mL) and extracted with EtOAc (200 mL Х 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (Petroleum ether : Ethyl acetate = 3 : 1) to produce methyl 4-[tert-butoxycarbonyl-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]amino]-6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-5-fluoro-pyridine-3-carboxylate (2.2 g, 3.15 mmol, 22.43% yield, 98% purity) as a yellow oil.

[1184] MS (ESI) m / z = 685.2 [M+H]+.

[1185] Step g.To a solution of methyl 4-[tert-butoxycarbonyl-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]amino]-6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-5-fluoro-pyridine-3-carboxylate (1.7 g, 2.48 mmol) in THF (30 mL) was added LiAlH4(2.5 M in THF, 1.09 mL) dropwise at 0 °C under an N2atmosphere and then the mixture was degassed and purged with N23 times. The mixture was stirred at 0 °C for 1 h under an N2atmosphere. LCMS showing the desired product was detected. H2O (2 mL) was slowly added to the reaction solution, then 15% NaOH (2 mL) and H2O (6 mL) were added respectively, and EtOAc (20 mL) and Na2SO4were added, then the mixture was stirred at 25 °C for 0.5 h. The mixture was filtered to produce a filtrate. The filtrate was diluted with H2O (100 mL) and extracted with EtOAc (200 mL Х 3). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce tert-butyl N-[2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-5-(hydroxymethyl)-4-pyridyl]-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]carbamate (1.8 g, crude) as a yellow solid.

[1186] MS (ESI) m / z = 657.9 [M+H]+.

[1187] Step h.To a solution of tert-butyl N-[2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-5-(hydroxymethyl)-4-pyridyl]-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]carbamate (2.3 g, crude) in DCM (50 mL) was added SOCl2(1.25 g, 10.51 mmol, 763.18 μL). The mixture was stirred at 0 °C for 1 h, and then to the mixture TFA (5 mL) was added. The resulting mixture was stirred at 25 °C for 12 h. LCMS showing the desired product was detected. The reaction mixture was concentrated under reduced pressure to produce 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyridin-4-amine (2 g, crude) as a yellow solid.

[1188] MS (ESI) m / z = 575.2 [M+H]+.

[1189] Step i.To a solution of 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-3-fluoro-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]pyridin-4-amine (1.5 g, 2.61 mmol) in dioxane (12 mL) and H2O (18 mL) was added Na2SO3(657.60 mg, 5.22 mmol). The mixture was stirred at 100 °C for 2 h. LCMS showing the desired product was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~100% Methanol / Dichloromethane@ 50 mL / min) to produce [6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-5-fluoro-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]amino]-3-pyridyl]methanesulfonic acid (1.5 g, 2.01 mmol, 76.90% yield, 83% purity) as a yellow solid.

[1190] MS (ESI) m / z = 621.4 [M+H]+.

[1191] Step j.To a solution of [6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-5-fluoro-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]amino]-3-pyridyl]methanesulfonic acid (1.6 g, 2.58 mmol) in CH3CN (10 mL) was added POCl3(10 mL). The mixture was stirred at 80 °C for 1 h. LCMS showing the desired product was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% Methanol / Dichloromethane@ 20 mL / min) to produce 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-7-fluoro-1-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]-3H-isothiazolo[4,3-c]pyridine 2,2-dioxide (800 mg, 1.22 mmol, 47.38% yield, 92% purity) as a yellow solid.

[1192] MS (ESI) m / z = 603.2 [M+H]+.

[1193] Step k.To a solution of 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-7-fluoro-1-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]-3H-isothiazolo[4,3-c]pyridine 2,2-dioxide (330 mg, 547.63 μmol) in DMF (5 mL) were added 2-bromoethyl(diphenyl)sulfonium;trifluoromethanesulfonate (485.52 mg, 1.10 mmol) and Et3N (166.24 mg, 1.64 mmol, 228.67 μL). The mixture was stirred at 25 °C for 2 h. LCMS showing the desired product was detected. The reaction mixture was concentrated under reduced pressure to produce a residue. The crude product was purified by Prep-HPLC (column: C18 150Х30mm;mobile phase: [Water(NH3H2O-NH4HCO3)-MeCN]; gradient:37%-77% B over 9 min) to produce 6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-7'-fluoro-1'-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]spiro[cyclopropane-1,3'-isothiazolo[4,3-c]pyridine] 2',2'-dioxide (71.11 mg, 113.12 μmol, 20.66% yield, 100% purity) as a yellow solid.

[1194] MS (ESI) m / z = 629.4 [M+H]+;1H NMR (DMSO-d6) = 8.65 (s, 1H), 8.24 (s, 1H), 8.16 (d,J= 1.2 Hz, 1H), 7.58 (d,J= 8.0 Hz, 2H), 7.50 (d,J= 8.0 Hz, 2H), 5.16 (s, 2H), 4.45 (td,J= 13.2, 6.8 Hz, 1H), 3.77 (s, 3H), 2.16-2.11 (m, 2H), 2.09-2.05 (m, 2H), 1.67-1.53 (m, 1H), 1.40 (d,J= 6.8 Hz, 6H), 1.10-1.01 (m, 1H), 0.96-0.83 (m, 2H), 0.82-0.73 (m, 1H).

[1195]

[1196] Example 7

[1197] 6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1'-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]methyl]spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide

[1198]

[1199] Step a.To a solution of methyl 2,4-dichloropyrimidine-5-carboxylate (1.5 g, 7.25 mmol) and [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]methanamine (2.27 g, 7.25 mmol) in THF (20 mL) was added DIEA (2.81 g, 21.74 mmol, 3.79 mL), then the mixture was stirred at 0 °C for 4 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) showing a new spot was observed. The reaction mixture was partitioned between EtOAc (100 mL) and H2O (100 mL). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~50%Ethylacetate / Petroleum ether gradient @ 40 mL / min) to produce methyl 2-chloro-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]amino]pyrimidine-5-carboxylate (3 g, 5.46 mmol, 75.30% yield, 88% purity) as a yellow solid.

[1200] MS (ESI) m / z = 484.1 [M+H]+;1H NMR (DMSO-d6) = 9.04 (t,J= 6.4 Hz, 1H), 8.65 (s, 1H), 8.12 (s, 1H), 7.30 (d,J= 7.6 Hz, 1H), 7.22 (s, 1H), 7.02 (d,J= 7.6 Hz, 1H), 4.76 (d,J= 5.6 Hz, 2H), 4.08-3.95 (m, 1H), 3.86 (s, 3H), 3.79 (s, 3H), 1.31 (d,J= 6.4 Hz, 6H).

[1201] Step b.To a solution of methyl 2-chloro-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]amino]pyrimidine-5-carboxylate (2.9 g, 5.99 mmol) and (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boronic acid (2.33 g, 11.99 mmol) in THF (20 mL) and H2O (2 mL) were added K3PO4(3.82 g, 17.98 mmol) and ditert-butyl(cyclopenta-1,4-dien-1-yl)phosphane;dichloropalladium;iron (390.61 mg, 599.33 μmol), then the mixture was stirred at 90 °C for 16 h under an N2atmosphere. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 80 g SepaFlash® Silica Flash Column, Eluent of 0~50%Ethylacetate / Petroleum ether gradient @ 40 mL / min) to produce methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]amino]pyrimidine-5-carboxylate (2.81 g, 4.45 mmol, 74.27% yield, 94.66% purity) as a yellow solid.

[1202] MS (ESI) m / z = 598.3 [M+H]+.

[1203] Step c.To a solution of methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]amino]pyrimidine-5-carboxylate (2.80 g, 4.69 mmol) in THF (20 mL) was added LiAlH4(2.5 M in THF, 3.75 mL) dropwise at 0 °C, then the mixture was stirred at 0 °C for 1 h under an N2atmosphere. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) showing a new spot was observed. The reaction mixture was quenched by addition of H2O (0.2 mL) at 0 °C, and then diluted with NaOH (0.2 mL, 15%) and H2O (0.2 mL). Then, anhydrous Na2SO4was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to produce [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]amino]pyrimidin-5-yl]methanol (1.35 g, 2.20 mmol, 47.04% yield, 93% purity) as a yellow solid.

[1204] MS (ESI) m / z = 570.2 [M+H]+.

[1205] Step d.To a solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]amino]pyrimidin-5-yl]methanol (1.35 g, 2.37 mmol) in DCM (5 mL) was added SOCl2(563.96 mg, 4.74 mmol, 344.30 μL), then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]methyl]pyrimidin-4-amine (1.35 g, crude) as a yellow solid.

[1206] MS (ESI) m / z = 588.2 [M+H]+.

[1207] Step e.To a solution of 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-N-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]methyl]pyrimidin-4-amine (1.35 g, 2.30 mmol) in dioxane (2 mL) and H2O (3 mL) was added Na2SO3(578.73 mg, 4.59 mmol), then the mixture was stirred at 100 °C for 2 h. LCMS showing the desired mass was observed. TLC (SiO2, Dichloromethane: Methanol = 10: 1) showing two new spots were observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Methanol / Dichloromethane gradient @ 40 mL / min) to produce [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (compound 6, 0.5 g, 284.07 μmol, 12.37% yield, 36% purity) as a yellow solid.

[1208] MS (ESI) m / z = 634.4 [M+H]+.

[1209] Step f.To a mixture of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]amino]pyrimidin-5-yl]methanesulfonic acid (0.5 g, 789.09 μmol) in CH3CN (10 mL) was added POCl3(1.21 g, 7.89 mmol, 735.52 μL) at 0 °C, then the mixture was stirred at 80 °C for 2 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was slowly quenched with water (45 °C), then the pH was adjusted >7 with NaHCO3 (sat.). The mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 40 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to produce 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]methyl]-3H-isothiazolo[3,4-d]pyrimidine 2,2-dioxide (110 mg, 99.70 μmol, 12.64% yield, 55.8% purity) as a yellow solid.

[1210] MS (ESI) m / z = 616.2 [M+H]+.

[1211] Step g.To a solution of 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]methyl]-3H-isothiazolo[3,4-d]pyrimidine 2,2-dioxide (100 mg, 162.44 μmol) and TEA (49.31 mg, 487.31 μmol, 67.83 μL) in DMF (4 mL) was added 2-bromoethyl(diphenyl)sulfonium;trifluoromethanesulfonate (108.01 mg, 243.65 μmol), then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. The mixture was purified directly without any work-up. The mixture was purified by prep-HPLC(column: C18 150Х30mm;mobile phase: [Water(NH3·H2O-NH4HCO3)-MeCN];gradient:34%-74% B over 15 min) to produce 6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1'-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]methyl]spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide (19.16 mg, 29.86 μmol, 18.38% yield, 100% purity) as a white solid.

[1212] MS (ESI) m / z = 642.3 [M+H]+;1H NMR (CD3OD) = 8.61 (s, 1H), 8.33 (s, 1H), 7.88 (s, 1H), 7.44-7.30 (m, 2H), 7.25 (d,J= 7.6 Hz, 1H), 5.13 (s, 2H), 4.21-4.12 (m, 1H), 3.92 (s, 3H), 3.79 (s, 3H), 2.30-2.15 (m, 2H), 2.05-1.91 (m, 2H), 1.81-1.68 (m, 1H), 1.40 (d,J= 6.4 Hz, 6H), 1.13 (td,J= 7.2, 3.6 Hz, 2H), 1.01-0.83 (m, 2H).

[1213] Example 8

[1214] 6'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-methoxybenzyl)-1'H-spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide

[1215]

[1216] Example 8 was performed using a method that is the same as the one described in the synthesis of Example 7, except that in step a, [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-2-methoxy-phenyl]methanamine was used instead of [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]methanamine, to produce the target compound (18.68 mg, 28.31 μmol, 14.53% yield, 97.26% purity) as a white solid.

[1217] MS (ESI) m / z = 642.3 [M+H]+;1H NMR (CD3OD) = 8.57 (s, 1H), 8.31 (s, 1H), 7.92 (d, J = 1.2 Hz, 1H), 7.49 (d, J = 7.6 Hz, 1H), 7.17 (d, J = 1.2 Hz, 1H), 7.07 (dd, J = 7.6, 1.2 Hz, 1H), 5.13 (s, 2H), 4.63-4.53 (m, 1H), 3.91 (d, J = 5.2 Hz, 6H), 2.26-2.12 (m, 2H), 2.01-1.87 (m, 2H), 1.73 (dt, J = 8.4, 4.2 Hz, 1H), 1.46 (d, J = 6.8 Hz, 6H), 1.16-1.09 (m, 2H), 0.89-0.84 (m, 2H).

[1218] Example 9

[1219] 6'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(2-(difluoromethoxy)-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide

[1220]

[1221] Example 9 was performed using a method that is the same as the one described in the synthesis of Example 7, except that in step a, [3-(difluoromethoxy)-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl]methanamine was used instead of [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]methanamine, to produce the target compound (20.15 mg, 29.73 μmol, 18.63% yield, 97.20% purity) as a white solid.

[1222] MS (ESI) m / z = 678.2 [M+H]+.

[1223]

[1224] Example 10

[1225] 6'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,6-dimethylbenzyl)-1'H-spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide

[1226]

[1227] Example 10 was performed using a method that is the same as the one described in the synthesis of Example 7, except that in step a, [4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2,6-dimethylphenyl]methanamine was used instead of [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]methanamine, to produce the target compound (13.19 mg, 20.54 μmol, 31.51% yield, 99.62% purity) as a white solid.

[1228] MS (ESI) m / z = 640.1 [M+H]+;1H NMR (DMSO-d6) = 8.69 (s, 1H), 8.50 (s, 1H), 8.16 (d,J= 1.2 Hz, 1H), 7.23 (s, 2H), 5.14 (s, 2H), 4.58-4.42 (m, 1H), 3.87 (s, 3H), 2.45 (s, 6H), 2.00 (br d,J= 6.4 Hz, 4H), 1.81-1.74 (m, 1H), 1.41 (d,J= 6.4 Hz, 6H), 1.07 (m, 2H), 0.98-0.89 (m, 2H).

[1229]

[1230] Example 11

[1231] 6'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(2-((dimethylamino)methyl)-4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide

[1232]

[1233] Example 11 was performed using a method that is the same as the one described in the synthesis of Example 7, except that in step a, 1-[2-(aminomethyl)-5-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl]-N,N-dimethylmethanamine was used instead of [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]methanamine, to produce the target compound (17.32 mg, 25.90 μmol, 18.53% yield, 98.36% purity) as a white solid.

[1234] MS (ESI) m / z = 669.2 [M+H]+.

[1235]

[1236] Example 12

[1237] 6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1'-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methyl]spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide

[1238] [Rectified under Rule 91, 30.08.2024]

[1239] Step a.A mixture of 3,3-dibromo-1,1,1-trifluoro-propan-2-one (51.07 g, 189.26 mmol), NaOAc (15.53 g, 189.26 mmol) in H2O (500 mL) was degassed and purged with N23 times, and then the mixture was stirred at 100 °C for 1 h under an N2atmosphere. The mixture was cooled to 25 °C, a solution of methyl 3-bromo-4-formyl-benzoate (46 g, 189.26 mmol) and NH3·H2O (318.37 g, 2.27 mol, 90.84 mL, 25% purity) in MeOH (1500 mL) was added, then the mixture was stirred at 25 °C for 16 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 3: 1) showing a new spot was observed. The reaction mixture was diluted with H2O (500 mL) and extracted with EtOAc (500 mL Х 3). The combined organic layers were washed with brine (300 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 65 mL / min) to produce methyl 3-bromo-4-[4-(trifluoromethyl)-1H-imidazol-2-yl]benzoate (25 g, 60.15 mmol, 31.78% yield, 84% purity) as a yellow solid.

[1240] MS (ESI) m / z = 350.8 [M+H+2]+.

[1241] Step b.To a solution of methyl 3-bromo-4-[4-(trifluoromethyl)-1H-imidazol-2-yl]benzoate (24.5 g, 70.18 mmol) and bromomethylbenzene (18.00 g, 105.27 mmol) in DMF (200 mL) was added Cs2CO3(68.60 g, 210.54 mmol), then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 3: 1) showing a new spot was observed. The reaction mixture was partitioned between H2O (300 mL) and EtOAc (300 mL). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 65 mL / min) to produce methyl 4-[1-benzyl-4-(trifluoromethyl)imidazol-2-yl]-3-bromo-benzoate (19.2 g, 38.82 mmol, 55.31% yield, 88.8% purity) as a yellow oil.

[1242] MS (ESI) m / z = 440.8 [M+H+2]+.

[1243] Step c.To a solution of methyl 4-[1-benzyl-4-(trifluoromethyl)imidazol-2-yl]-3-bromo-benzoate (18.5 g, 42.12 mmol), but-3-yn-2-ol (5.90 g, 84.24 mmol, 6.60 mL) and CuI (8.02 g, 42.12 mmol) in Py (200 mL) and TEA (50 mL) was added Pd(dppf)Cl2·CH2Cl2(6.88 g, 8.42 mmol) under an N2atmosphere. The suspension was degassed and purged with N23 times. The mixture was stirred under N2at 100 °C for 16 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) showing a new spot was observed. The reaction was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 120 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to produce methyl 4-[1-benzyl-4-(trifluoromethyl)imidazol-2-yl]-3-(3-hydroxybut-1-ynyl)benzoate (3.0 g, 5.39 mmol, 12.80% yield, 77% purity) as a yellow oil.

[1244] MS (ESI) m / z = 429.1 [M+H]+.

[1245] Step d.To a solution of methyl 4-[1-benzyl-4-(trifluoromethyl)imidazol-2-yl]-3-(3-hydroxybut-1-ynyl)benzoate (2.3 g, 5.37 mmol) in THF (50 mL) was added Pd / C (230.00 mg, 216.12 μmol, 10% purity) under an Ar atmosphere. The suspension was degassed and purged with H23 times. The mixture was stirred under an H2atmosphere (50 Psi) at 50 °C for 16 h. LCMS showing the desired mass was observed. The reaction mixture was filtered, the filtered cake was washed 3 times with methanol (20 mL), and the filtrate was concentrated under reduced pressure to produce methyl 3-(3-hydroxybutyl)-4-[4-(trifluoromethyl)-1H-imidazol-2-yl]benzoate (3.43 g, crude) as a yellow solid.

[1246] MS (ESI) m / z = 343.0 [M+H]+.

[1247] Step e.To a solution of methyl 3-(3-hydroxybutyl)-4-[4-(trifluoromethyl)-1H-imidazol-2-yl]benzoate (2.5 g, 7.30 mmol) and PPh3(7.86 g, 29.96 mmol) in THF (20 mL) was added DEAD (5.11 g, 29.33 mmol, 5.33 mL), then the mixture was stirred at 25 °C for 1 h under an N2atmosphere. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to produce methyl 5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepine-9-carboxylate (1.71 g, 4.69 mmol, 64.26% yield, 89% purity) as a yellow solid.

[1248] MS (ESI) m / z = 325.1 [M+H]+.

[1249] Step f.A solution of methyl 5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepine-9-carboxylate (1.71 g, 5.27 mmol) in THF (20 mL) was degassed in vacuo and purged with N23 times, then LiAlH4(2.5 M in THF, 3.16 mL) was added dropwise at 0 °C, then the mixture was stirred at 0 °C for 0.5 h under an N2atmosphere. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) showing a new spot was observed. The reaction mixture was quenched by addition H2O (0.6 mL) at 0 °C, and then diluted with NaOH (0.6 mL, 15%) and H2O (0.6 mL). Then, anhydrous Na2SO4(3 g) was added, and the mixture was filtered. The filtrate was concentrated in vacuo to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~100% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to produce [5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methanol (1.38 g, 4.01 mmol, 75.96% yield, 86% purity) as a yellow solid.

[1250] MS (ESI) m / z = 297.0 [M+H]+.

[1251] Step g.To a solution of [5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methanol (1.5 g, 5.06 mmol) in THF (20 mL) were added methylsulfonyl methanesulfonate (2.65 g, 15.19 mmol) and TEA (1.54 g, 15.19 mmol, 2.11 mL), then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. The reaction mixture was partitioned between EtOAc (100 mL) and H2O (50 mL). The organic phase was separated, washed with brine (20 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce [5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methyl methanesulfonate (1.9 g, 1.83 mmol, 36.09% yield, 36% purity) as a yellow solid, which was directly used for the next step without further purification.

[1252] MS (ESI) m / z = 375.1 [M+H]+.

[1253] Step h.To a solution of [5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methyl methanesulfonate (1.9 g, 5.08 mmol) in DMF (15 mL) were added Cs2CO3(4.96 g, 15.23 mmol) and tert-butyl N-tert-butoxycarbonylcarbamate (1.65 g, 7.61 mmol), then the mixture was stirred at 30 °C for 3 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 3: 1) showing a new spot was observed. The reaction mixture was partitioned between EtOAc (200 mL) and H2O (100 mL). The organic phase was separated, washed with brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 20 g SepaFlash® Silica Flash Column, Eluent of 0~20% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to produce tert-butyl N-tert-butoxycarbonyl-N-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methyl]carbamate (0.8 g, 1.24 mmol, 24.49% yield, 77% purity) as a yellow oil.

[1254] MS (ESI) m / z = 496.2 [M+H]+.

[1255] Step i.To a solution of tert-butyl N-tert-butoxycarbonyl-N-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methyl]carbamate (800 mg, 1.61 mmol) in DCM (3 mL) was added HCl / dioxane (2 M, 807 μL), then the mixture was stirred at 25 °C for 16 h. LCMS showing the desired mass was observed. The reaction was concentrated under reduced pressure to produce [5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methanamine (0.6 g, crude, HCl) as a yellow solid, which was directly used for next step without further purification.

[1256] MS (ESI) m / z = 296.1 [M+H]+.

[1257] Step j.To a solution of [5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methanamine (570.59 mg, 1.93 mmol, HCl) and DIEA (749.18 mg, 5.80 mmol, 1.01 mL) in THF (10 mL) was added methyl 2,4-dichloropyrimidine-5-carboxylate (0.4 g, 1.93 mmol) at 0 °C, then the mixture was stirred at 25 °C for 16 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to produce methyl 2-chloro-4-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]amino]pyrimidine-5-carboxylate (0.3 g, 547.38 μmol, 28.33% yield, 85% purity) as a yellow solid.

[1258] MS (ESI) m / z = 466.1 [M+H]+.

[1259] Step k.To a solution of methyl 2-chloro-4-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]amino]pyrimidine-5-carboxylate (270 mg, 579.58 μmol) and (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boronic acid (224.87 mg, 1.16 mmol) in THF (10 mL) and H2O (1 mL) were added ditert-butyl(cyclopenta-1,4-dien-1-yl)phosphane;dichloropalladium;iron (37.77 mg, 57.96 μmol) and K3PO4(369.08 mg, 1.74 mmol), then the reaction mixture was stirred at 90 °C for 16 h under an N2atmosphere. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to produce methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]amino]pyrimidine-5-carboxylate (210 mg, 307.99 μmol, 53.14% yield, 85% purity) as a yellow solid.

[1260] MS (ESI) m / z = 580.4 [M+H]+.

[1261] Step l.To a solution of methyl 2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]amino]pyrimidine-5-carboxylate (210 mg, 362.34 μmol) in THF (5 mL) was degassed in vacuo and purged with N23 times, then LiAlH4(2.5 M, 289.87 μL) was added dropwise at 0 °C, then the mixture was stirred at 0 °C for 1 h under an N2atmosphere. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) showing a new spot was observed. The reaction mixture was quenched by addition H2O (0.3 mL) at 0 °C, and then diluted with NaOH (0.3 mL, 15%) and H2O (0.3 mL). Then, anhydrous Na2SO4(3.0 g mL) was added, and the mixture was filtered. The filtrate was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethyl acetate / Petroleum ether gradient @ 40 mL / min) to produce [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]amino]pyrimidin-5-yl]methanol (110 mg, 161.54 μmol, 44.58% yield, 81% purity) as a yellow solid.

[1262] MS (ESI) m / z = 552.2 [M+H]+.

[1263] Step m.To a solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]amino]pyrimidin-5-yl]methanol (110 mg, 199.43 μmol) in DCM (5 mL) was added SOCl2(47.45 mg, 398.87 μmol, 28.97 μL), then the mixture was stirred at 25 °C for 1 h. LCMS showing the desired mass was observed. The reaction mixture was concentrated under reduced pressure to produce 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-N-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methyl]pyrimidin-4-amine (110 mg, 162.10 μmol, 81.28% yield, 84% purity) as a yellow solid, which was directly used for next step without further purification.

[1264] MS (ESI) m / z = 570.2 [M+H]+.

[1265] Step n.To a solution of 5-(chloromethyl)-2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-N-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methyl]pyrimidin-4-amine (110 mg, 192.98 μmol) in dioxane (2 mL) and H2O (3 mL) was added Na2SO3(48.65 mg, 385.96 μmol), then the mixture was stirred at 100 °C for 2 h. LCMS showing the desired mass was observed. TLC (SiO2, Dichloromethane: Methanol = 10: 1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~10% Methanol: Dichloromethane gradient @ 40 mL / min) to produce [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]amino]pyrimidin-5-yl]methanesulfonic acid (120 mg, 120.85 μmol, 62.62% yield, 62% purity) as a yellow solid.

[1266] MS (ESI) m / z = 616.3 [M+H]+.

[1267] Step o.A solution of [2-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-4-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]amino]pyrimidin-5-yl]methanesulfonic acid (110 mg, 178.68 μmol) in CH3CN (2 mL) was degassed in vacuo and purged with N23 times, then POCl3(1.65 g, 10.73 mmol, 1 mL) was added dropwise, then the mixture was heated to 80 °C and stirred at 80 °C for 2 h. LCMS showing the desired mass was observed. TLC (SiO2, Petroleum ether: Ethyl acetate = 1: 1) showing a new spot was observed. The reaction mixture was concentrated under reduced pressure to remove POCl3(1.65 g, 10.73 mmol, 1 mL) and produce a residue. The residue was quenched with water (100 mL, 45 °C) slowly, and the pH was adjusted to >7 with saturated NaHCO3(50 mL) and extracted with EtOAc (100 mL Х 3). The combined organic layers were washed with brine (150 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to produce a residue. The residue was purified by flash silica gel chromatography (ISCO®; 12 g SepaFlash® Silica Flash Column, Eluent of 0~50% Ethylacetate / Petroleum ether gradient @ 40 mL / min) to produce 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methyl]-3H-isothiazolo[3,4-d]pyrimidine 2,2-dioxide (52 mg, 33.07 μmol, 18.51% yield, 38% purity) as a yellow solid.

[1268] MS (ESI) m / z = 598.1 [M+H]+.

[1269] Step p.To a solution of 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methyl]-3H-isothiazolo[3,4-d]pyrimidine 2,2-dioxide (52 mg, 87.01 μmol) in DMF (5 mL) were added 2-bromoethyl(diphenyl)sulfonium;trifluoromethanesulfonate (77.15 mg, 174.03 μmol) and Et3N (26.41 mg, 261.04 μmol, 36.33 μL), then the mixture was stirred at 25 °C for 2 h. LCMS showing the desired mass was observed. The reaction mixture was filtered and the filtrate was directly purified by Prep-HPLC (column: C18 150Х40mm; mobile phase: [Water(NH3·H2O-NH4HCO3)-MeCN]; gradient:39%-79% B over 9 min) to produce 6'-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1'-[[5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methyl]spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide (3.8 mg, 6.01 μmol, 6.90% yield, 98.6% purity) as a white solid.

[1270] MS (ESI) m / z = 624.2 [M+H]+;1H NMR (CD3OD) = 8.60 (s, 1H), 8.32 (s, 1H), 7.81 (d,J= 1.2 Hz, 1H), 7.67-7.63 (m, 1H), 7.58-7.52 (m, 1H), 7.49 (s, 1H), 5.11 (s, 2H), 4.06 (td,J= 11.6, 6.0 Hz, 1H), 3.91 (s, 3H), 2.82-2.71 (m, 1H), 2.65-2.53 (m, 1H), 2.40 (td,J= 12.0, 6.0 Hz, 1H), 2.24-2.19 (m, 2H), 2.17-2.08 (m, 1H), 2.00-1.95 (m, 2H), 1.75-1.66 (m, 1H), 1.56 (d,J= 6.8 Hz, 3H), 1.13-1.09 (m, 2H), 0.90-0.85 (m, 2H).

[1271]

[1272]

[1273] Example 13

[1274] 1'-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)-2-methoxybenzyl)-6'-(2-isopropylpyridin-3-yl)-1'H-spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide

[1275]

[1276] Example 13 was performed using a method that is the same as the one described in the synthesis of Example 7, except that in step a, [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-2-methoxy-phenyl]methanamine was used instead of [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]methanamine and in step b, (2-isopropylpyridin-3-yl)boronic acid was used instead of (4-cyclopropyl-6-methoxy-pyrimidin-5-yl)boronic acid, to produce the target compound (13.32 mg, 21.74 μmol, 19.53% yield, 97.77% purity) as a white solid.

[1277] MS (ESI) m / z = 613.2 [M+H]+.

[1278]

[1279] Example 14

[1280] 6'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(2-methoxy-4-(1-(1-methylazetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide

[1281]

[1282] Example 14 was performed using a method that is the same as the one described in the synthesis of Example 7, except that in step a, [2-methoxy-4-(1-(1-methylazetidin-3-yl)-4-(trifluoromethyl)-1H-imidazol-2-yl)phenyl]methanamine was used instead of [4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]-3-methoxy-phenyl]methanamine, to produce the target compound (14.32 mg, 21.41 μmol, 16.66% yield, 97.56% purity) as a white solid.

[1283] MS (ESI) m / z = 669.1 [M+H]+.

[1284]

[1285] Example 15

[1286] 6'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclobutane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide

[1287]

[1288] Step a.To a solution of 6-(4-cyclopropyl-6-methoxy-pyrimidin-5-yl)-1-[[4-[1-isopropyl-4-(trifluoromethyl)imidazol-2-yl]phenyl]methyl]-3H-isothiazolo[3,4-d]pyrimidine 2,2-dioxide (50 mg, 85.38 μmol) in DMF (1 mL) was added K2CO3(118 mg, 853.8 μmol) and 1,3-dibromopropane (48.12 mg, 256.14 μmol). The mixture was stirred at 80 °C for 2 h. LCMS showing the desired mass was detected. The reaction mixture was dissolved in EtOAc (5 mL), washed with water (5 mL) and brine (5 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to produce the residue. The residue was purified by reversed phase column (column: Boston Prime C18 150*30mm*5um;mobile phase: [water(FA)-ACN];gradient:50%-70% B over 10 min) to produce 6'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclobutane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide (4.2 mg, 6.67 μmol, 7.82% yield, 96% purity) as a yellow solid.

[1289] MS (ESI) m / z = 626.2 [M+H]+.

[1290]

[1291] Example 16

[1292] 6'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclopentane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide

[1293]

[1294] Example 16 was performed using a method that is the same as the one described in the synthesis of Example 15, except that in step a, 1,4-dibromobutane was used instead of 1,3-dibromopropane, to produce the target compound (20.35 mg, 31.81 μmol, 24.62% yield, 97.02% purity) as a white solid.

[1295] MS (ESI) m / z = 642.3 [M+H]+.

[1296]

[1297] Example 17

[1298] 6'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-(4-(1-isopropyl-4-(trifluoromethyl)-1H-imidazol-2-yl)benzyl)-1'H-spiro[cyclohexane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide

[1299]

[1300] Example 17 was performed using a method that is the same as the one described in the synthesis of Example 15, except that in step a, 1,5-dibromopentane was used instead of 1,3-dibromopropane, to produce the target compound (11.32 mg, 17.31 μmol, 22.43% yield, 97.10% purity) as a white solid.

[1301] MS (ESI) m / z = 654.3 [M+H]+.

[1302]

[1303] Example 18

[1304] 6'-(4-cyclopropyl-6-methoxypyrimidin-5-yl)-1'-((2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methyl)-1'H-spiro[cyclopropane-1,3'-isothiazolo[3,4-d]pyrimidine] 2',2'-dioxide

[1305]

[1306] Example 18 was performed using a method that is the same as the one described in the synthesis of Example 12, except that in step j, (2-(trifluoromethyl)-6,7-dihydro-5H-benzo[c]imidazo[1,2-a]azepin-9-yl)methanamine was used instead of [5-methyl-2-(trifluoromethyl)-6,7-dihydro-5H-imidazo[2,1-a][2]benzazepin-9-yl]methanamine, to produce the target compound (16.32 mg, 26.77 μmol, 26.42% yield, 98.20% purity) as a white solid.

[1307] MS (ESI) m / z = 610.2 [M+H]+.

[1308]

[1309] Biological assays

[1310] Ubiquitin specific peptidase 1 (USP1) belongs to a large group of ubiquitin-specific proteases capable of cleaving ubiquitin from other proteins. Ubiquitin-Rhodamin 110 is a fluorogenic substrate for ubiquitin hydrolases based on the C-terminus derivatization of ubiquitin with Rhodamin 110. In the conjugated form, the energy emitted from fluorochrome Rhodamin is quenched. Upon proteolysis, Rhodamin is no longer quenched and emits fluorescence with an excitation / emission maxima of 480 / 540 nm. The increase in fluorescence is proportional to the DUB activity.

[1311] To determine the effect of an inhibitor on USP1 activity, the enzyme should be preincubated with or without the test inhibitor prior to adding the Ub-Rhodamin 110 (Manufacturer - R&D systems, Inc., Catalog # - U-555-050) substrate to the reaction.

[1312] The compounds of Examples 1 to 38 were tested in the above-mentioned enzyme potency assay and the results are shown in the following table:

[1313] The compounds of Examples 1 to 18 were tested in the above-mentioned enzyme potency assay and results are shown in the following table:

[1314] Note:

[1315]

[1316] As shown in the above Table, it is demonstrated that the tested compounds exhibit good activity in inhibiting USP1.

[1317]

[1318] Colony formation assay

[1319] Against BRCA1 mutant human breast cancer UWB1.289 cell line

[1320] UWB1.289 cells were cultured in complete media (50% RMPI-1640 + 50% MEGM; MEBM basal medium supplemented with SingleQuot additives + 3% FBS + 1% P / S). The cells were cultured in 37°C, 5% CO2 incubator. When the cells reached confluency of 80%, cells were trypsinized with 0.25% Trypsin (Gibco, 25200-056) and centrifuged at 1000rpm for 3 minutes. The supernatant was discarded, and cell pellet were re-suspended in fresh complete medium. The cells were seeded into a culture flask at an appropriate proportion.

[1321] UWB1.289 cells were seeded 2000 cells / well on 6-well plate (Corning, 3506) and allowed to attach on plate for overnight. On the next day, the cells were treated with serially diluted compounds or 0.2% DMSO. The compounds were serially diluted in 5 folds in DMSO with highest concentration of 10mM. The compound was diluted 1 / 500 in complete medium for the cell treatment. The cells were allowed to grow for 14 days and media was change was carried out every 3 or 4 days with media containing appropriate concentration of DMSO or compounds. On day 14 the cells were fixed and stained with Coomassie blue for 20 minutes at room temperature. The plates were washed with distilled water for three times. The plates were imaged with ChemiDoc (Bio-Rad) and density of colonies were measured. The inhibitory rate of compounds on cell clonogenicity was plotted using cell survival rate against the various compound concentration. Results: IC50 values determined for selected compounds of the invention are presented in Table below.

[1322] Note:

[1323]

[1324] As shown in the above Table, it is demonstrated that the tested compounds exhibit good activity in inhibiting USP1.

[1325]

[1326] While the compounds, compositions, formulations, and methods of this disclosure have been described in terms of specific embodiments, it will be apparent to those skilled in the art that variations or modifications may be applied to the compounds, compositions, formulations, and methods described herein without departing from the spirit and scope of this disclosure. All such variations or modifications apparent to those skilled in the art are deemed to be within the spirit and scope of this disclosure as defined by the appended claims.

[1327]

[1328] The present disclosure provides the following embodiments:

[1329] Embodiment 1. A compound of the following Formula (I):

[1330]

[1331] (I)

[1332] wherein:

[1333] A is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1334] L is selected from the group consisting of -(C2-C6alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C2-C6alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, -(C1-C6alkylene)-N(C1-C6alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1335] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto;

[1336] q is an integer between 1 to 5;

[1337] B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1338] each of W1and W2is independently selected from N and CR3, wherein each of R3is independently selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1339] each of X and Y is independently selected from the group consisting of a single bond, sulfur, oxygen, -N(R1)-, -C(O)-, and -CH(R2)-, wherein each of R1and R2is independently selected from the group consisting of hydrogen, C1-C6alkyl, hydroxy, halogen, and C1-C6alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[1340] each of n and m is independently an integer between 0 to 7, provided that when X and Y both are a single bond, m+n is greater than or equal to 2; and when either X or Y is a single bond, m+n is greater than or equal to 1,

[1341] or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[1342]

[1343] Embodiment 2. The compound according to embodiment 1, wherein the compound is a compound represented by Formula (Ia):

[1344]

[1345] (Ia)

[1346] wherein:

[1347] A is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1348] L is selected from the group consisting of -(C2-C6alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C2-C6alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, -(C1-C6alkylene)-N(C1-C6alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1349] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto;

[1350] q is an integer between 1 to 5;

[1351] B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1352] each of W1and W2is independently selected from N and CR3, wherein each of R3is independently selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[1353] n is an integer between 2 to 7.

[1354]

[1355] Embodiment 3. The compound according to any one of embodiments 1 to 2, wherein the compound is a compound represented by Formula (Ib):

[1356]

[1357] (Ib)

[1358] wherein:

[1359] A is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1360] L is selected from the group consisting of -(C2-C6alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C2-C6alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, -(C1-C6alkylene)-N(C1-C6alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1361] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto;

[1362] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1363] W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1364] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[1365] n is an integer between 2 to 7.

[1366]

[1367] Embodiment 4. The compound according to any one of embodiments 1 to 3, wherein A is selected from the group consisting of:

[1368]

[1369]

[1370]

[1371]

[1372]

[1373] each of Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, and Ra7is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, RL1,

[1374]

[1375] wherein Raais selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromom, and iodo;

[1376] L is selected from the group consisting of -phenylene-, , , and , wherein said phenylene is optionally substituted with one or more selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -CH2N(CH3)2, -CH2N(CH2CH3)2, -CH2N(CH(CH3)2)2, and RL2; and

[1377] RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 6-9 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, and mercapto.

[1378]

[1379] Embodiment 5. The compound according to any one of embodiments 1 to 3, wherein the compound is a compound represented by Formula (Ic-1):

[1380]

[1381] (Ic-1)

[1382] wherein:

[1383] each of Ra1, Ra2, and Ra3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1384] each of RL21, RL22, RL23, and RL24is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, and -(C1-C6alkylene)-N(C1-C6alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1385] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1386] W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[1387] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[1388] n is an integer between 2 to 7.

[1389]

[1390] Embodiment 6. The compound according to any one of embodiments 1 to 3 and 5, wherein each of Ra1, Ra2, and Ra3is independently selected from the group consisting of hydrogen, C1-C6alkyl, oxo, and 3-5 membered heterocyclyl, wherein each of said alkyl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;

[1391] each of RL21, RL22, RL23, and RL24is independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, and -(C1-C6alkylene)-N(C1-C6alkyl)2, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,

[1392] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy;

[1393] W1is selected from N and CR3, wherein R3is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, fluoro, chloro, bromo, iodo, and trifluoromethyl;

[1394] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy; and

[1395] n is an integer between 2 to 5.

[1396]

[1397] Embodiment 7. The compound according to any one of embodiments 1 to 3, and 5, wherein each of Ra1, Ra2, and Ra3is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl,

[1398]

[1399] Raais selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromom, and iodo;

[1400] each of RL21, RL22, RL23, and RL24is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -CH2N(CH3)2, -CH2N(CH2CH3)2, and -CH2N(CH(CH3)2)2;

[1401] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy;

[1402] W1is selected from N and CR3, wherein R3is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, fluoro, chloro, bromo, iodo, and trifluoromethyl;

[1403] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy; and

[1404] n is an integer between 2 to 5.

[1405]

[1406] Embodiment 8. The compound according to any one of embodiments 1 to 3, wherein the compound is a compound represented by Formula (Ic-2):

[1407]

[1408] (Ic-2)

[1409] wherein:

[1410] each of Ra2, Ra3, and Ra4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1411] each of RL21, RL22, RL23, and RL24is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, and -(C1-C6alkylene)-N(C1-C6alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1412] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1413] W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[1414] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[1415] n is an integer between 2 to 7.

[1416]

[1417] Embodiment 9. The compound according to any one of embodiments 1 to 3, wherein the compound is a compound represented by Formula (Ic-3):

[1418]

[1419] (Ic-3)

[1420] wherein:

[1421] each of Ra1, Ra2, and Ra3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1422] each of RL21, RL22, RL23, and RL24is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, and -(C1-C6alkylene)-N(C1-C6alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1423] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1424] W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[1425] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[1426] n is an integer between 2 to 7.

[1427]

[1428] Embodiment 10. The compound according to any one of embodiments 1 to 3, wherein the compound is a compound represented by Formula (Ic-4):

[1429]

[1430] (Ic-4)

[1431] wherein:

[1432] wherein:

[1433] each of Ra1, Ra2, Ra3, Ra4, and Ra5is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1434] each of RL21, RL22, RL23, and RL24is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, and -(C1-C6alkylene)-N(C1-C6alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1435] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1436] W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[1437] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[1438] n is an integer between 2 to 7.

[1439]

[1440] Embodiment 11. The compound according to any one of embodiments 1 to 3, wherein the compound is a compound represented by Formula (Ic-5):

[1441]

[1442] (Ic-5)

[1443] wherein:

[1444] each of Ra2and Ra3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1445] each of RL11, RL12, and RL13is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto;

[1446] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1447] W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1448] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[1449] n is an integer between 2 to 7.

[1450]

[1451] Embodiment 12. The compound according to any one of embodiments 1 to 3, wherein the compound is a compound represented by Formula (Ic-6):

[1452]

[1453] (Ic-6)

[1454] wherein:

[1455] each of Ra1, Ra2, and Ra3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1456] each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1457] W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;

[1458] W3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; and

[1459] n is an integer between 2 to 7.

[1460]

[1461] Embodiment 13. The compound according to embodiments 1 to 3, wherein the compound is selected from the group consisting of:

[1462] 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18

[1463] .

[1464]

[1465] Embodiment 14. A pharmaceutical composition for treating or preventing diseases or disorders mediated by USP1, preferably cancer, more preferably lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; skin cancer including melanoma, kidney cancer, colon cancer, osteosarcoma, pancreatic cancer, bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; or uterine cancer, comprising the compound according to any one of preceding embodiments, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof; and a pharmaceutically acceptable carrier(s) or excipient(s).

[1466]

[1467] Embodiment 15. The pharmaceutical composition according to claim 14, wherein the composition is administered separately, sequentially or simultaneously with additional DNA damage response (DDR) targeting anti-cancer agent(s), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (e.g., nedisertib or peposertib), AZD7648), CHK1 / 2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (e.g., MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

[1468]

[1469] Embodiment 16. A compound according to any one of embodiments 1 to 13, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof for use in the prevention or treatment of diseases or disorders mediated by USP1, preferably cancer, more preferably lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; skin cancer including melanoma, kidney cancer, colon cancer, osteosarcoma, pancreatic cancer, bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; or uterine cancer.

[1470]

[1471] Embodiment 17. The compound according to embodiment 16, wherein the compound is administered separately, sequentially or simultaneously with additional DNA damage response (DDR) targeting anti-cancer agent(s), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

[1472]

[1473] Embodiment 18. A method of treating or preventing diseases or disorders mediated by USP1 in a subject, comprising administering to the subject at least one compound according to any one of embodiments 1 to 13, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.

[1474]

[1475] Embodiment 19. The method of embodiment 18, wherein the diseases or disorders mediated by USP1 are cancer, preferably lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; skin cancer including melanoma, kidney cancer, colon cancer, osteosarcoma, pancreatic cancer, bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; or uterine cancer.

[1476]

[1477] Embodiment 20. The method of any one of embodiments 18 to 19, further comprising administering to the subject additional DDR targeting anti-cancer agent(s), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

Claims

1.A compound of the following Formula (I):(I)wherein:A is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;L is selected from the group consisting of -(C2-C6alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C2-C6alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, -(C1-C6alkylene)-N(C1-C6alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto;q is an integer between 1 to 5;B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;each of W1and W2is independently selected from N and CR3, wherein each of R3is independently selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;each of X and Y is independently selected from the group consisting of a single bond, sulfur, oxygen, -N(R1)-, -C(O)-, and -CH(R2)-, wherein each of R1and R2is independently selected from the group consisting of hydrogen, C1-C6alkyl, hydroxy, halogen, and C1-C6alkoxy, wherein each of said alkyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; andeach of n and m is independently an integer between 0 to 7, provided that when X and Y both are a single bond, m+n is greater than or equal to 2; and when either X or Y is a single bond, m+n is greater than or equal to 1,or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.2.The compound according to claim 1, wherein the compound is a compound represented by Formula (Ia):(Ia)wherein:A is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;L is selected from the group consisting of -(C2-C6alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C2-C6alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, -(C1-C6alkylene)-N(C1-C6alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto;q is an integer between 1 to 5;B is 5-12 membered heteroaryl, wherein said heteroaryl is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;each of W1and W2is independently selected from N and CR3, wherein each of R3is independently selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; andn is an integer between 2 to 7.3.The compound according to any one of claims 1 to 2, wherein the compound is a compound represented by Formula (Ib):(Ib)wherein:A is 5-12 membered heteroaryl or 5-12 membered heterocyclyl, wherein each of said heteroaryl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, 3-6 membered heterocyclyl, and RL1, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;L is selected from the group consisting of -(C2-C6alkynylene)-, -(6-14 membered arylene)-, -(7-11 membered polycyclic cycloalkylene)-, -(C2-C6alkynylene)-NH-, -(6-14 membered arylene)-NH-, and -(7-11 membered polycyclic cycloalkylene)-NH-, wherein said arylene is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, -(C1-C6alkylene)-N(C1-C6alkyl)2, and RL2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;RL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 5-10 membered carbocyclic or heterocyclic group, wherein said carbocyclic or heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto;each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;W3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; andn is an integer between 2 to 7.4.The compound according to any one of claims 1 to 3, wherein A is selected from the group consisting of:each of Ra1, Ra2, Ra3, Ra4, Ra5, Ra6, and Ra7is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl, RL1,;wherein Raais selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromom, and iodo;L is selected from the group consisting of -phenylene-,,, and, wherein said phenylene is optionally substituted with one or more selected from methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -CH2N(CH3)2, -CH2N(CH2CH3)2, -CH2N(CH(CH3)2)2, and RL2; andRL1and RL2, taken together with the atoms to which each RL1and RL2is attached, form a saturated or unsaturated 6-9 membered heterocyclic group, wherein said heterocyclic group is optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, and mercapto.5.The compound according to any one of claims 1 to 3, wherein the compound is a compound represented by Formula (Ic-1):(Ic-1)wherein:each of Ra1, Ra2, and Ra3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;each of RL21, RL22, RL23, and RL24is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, and -(C1-C6alkylene)-N(C1-C6alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; andW3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; andn is an integer between 2 to 7.6.The compound according to any one of claims 1 to 3 and 5, wherein each of Ra1, Ra2, and Ra3is independently selected from the group consisting of hydrogen, C1-C6alkyl, oxo, and 3-5 membered heterocyclyl, wherein each of said alkyl and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen;each of RL21, RL22, RL23, and RL24is independently selected from the group consisting of hydrogen, C1-C6alkyl, C1-C6alkoxy, and -(C1-C6alkylene)-N(C1-C6alkyl)2, wherein each of said alkyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, and halogen,each of Rb1and Rb3is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy;W1is selected from N and CR3, wherein R3is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, fluoro, chloro, bromo, iodo, and trifluoromethyl;W3is selected from N and CR4, wherein each of R4is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy; andn is an integer between 2 to 5.7.The compound according to any one of claims 1 to 3 and 5, wherein each of Ra1, Ra2, and Ra3is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, trifluoromethyl,Raais selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, fluoro, chloro, bromom, and iodo;each of RL21, RL22, RL23, and RL24is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, isopropyl, trifluoromethyl, methoxy, ethoxy, n-propoxy, isopropoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, -CH2N(CH3)2, -CH2N(CH2CH3)2, and -CH2N(CH(CH3)2)2;each of Rb1and Rb3is independently selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy;W1is selected from N and CR3, wherein R3is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, fluoro, chloro, bromo, iodo, and trifluoromethyl;W3is selected from N and CR4, wherein each of R4is selected from hydrogen, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, trifluoromethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, methoxy, ethoxy, n-propoxy, and isopropoxy; andn is an integer between 2 to 5.8.The compound according to any one of claims 1 to 3, wherein the compound is a compound represented by Formula (Ic-2):(Ic-2)wherein:each of Ra2, Ra3, and Ra4is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;each of RL21, RL22, RL23, and RL24is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, and -(C1-C6alkylene)-N(C1-C6alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; andW3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; andn is an integer between 2 to 7.9.The compound according to any one of claims 1 to 3, wherein the compound is a compound represented by Formula (Ic-3):(Ic-3)wherein:each of Ra1, Ra2, and Ra3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;each of RL21, RL22, RL23, and RL24is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, and -(C1-C6alkylene)-N(C1-C6alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; andW3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; andn is an integer between 2 to 7.10.The compound according to any one of claims 1 to 3, wherein the compound is a compound represented by Formula (Ic-4):(Ic-4)wherein:wherein:each of Ra1, Ra2, Ra3, Ra4, and Ra5is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;each of RL21, RL22, RL23, and RL24is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, and -(C1-C6alkylene)-N(C1-C6alkyl)2, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; andW3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; andn is an integer between 2 to 7.11.The compound according to any one of claims 1 to 3, wherein the compound is a compound represented by Formula (Ic-5):(Ic-5)wherein:each of Ra2and Ra3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;each of RL11, RL12, and RL13is selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto;each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;W3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; andn is an integer between 2 to 7.12.The compound according to any one of claims 1 to 3, wherein the compound is a compound represented by Formula (Ic-6):(Ic-6)wherein:each of Ra1, Ra2, and Ra3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, mercapto, oxo, and 3-6 membered heterocyclyl, wherein each of said alkyl, cycloalkyl, alkenyl, alkoxy, and heterocyclyl is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;each of Rb1and Rb3is independently selected from the group consisting of hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;W1is selected from N and CR3, wherein R3is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, C2-C6alkynyl, hydroxy, C1-C6alkoxy, amino, or mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, alkynyl and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl;W3is selected from N and CR4, wherein each of R4is selected from hydrogen, C1-C6alkyl, carbamoyl, acetamido, 3-10 membered cycloalkyl, halogen, cyano, C2-C6alkenyl, hydroxy, C1-C6alkoxy, amino, and mercapto, wherein each of said alkyl, cycloalkyl, alkenyl, and alkoxy is independently optionally substituted with one or more selected from C1-C6alkyl, halogen, cyano, hydroxy, amino, mercapto, and carbamoyl; andn is an integer between 2 to 7.13.The compound according to any one of claims 1 to 3, wherein the compound is selected from the group consisting of:14.A pharmaceutical composition for preventing or treating diseases or disorders mediated by USP1, preferably cancer, more preferably lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; skin cancer including melanoma, kidney cancer, colon cancer, osteosarcoma, pancreatic cancer, bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; or uterine cancer, comprising the compound according to any one of claims 1 to 13, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof; and a pharmaceutically acceptable carrier(s) or excipient(s).15.The pharmaceutical composition according to claim 14, wherein the composition is administered separately, sequentially or simultaneously with additional DNA damage response (DDR) targeting anti-cancer agent(s), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).16.A compound according to any one of claims 1 to 13, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof for use in the prevention or treatment of diseases or disorders mediated by USP1, preferably cancer, more preferably lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; skin cancer including melanoma, kidney cancer, colon cancer, osteosarcoma, pancreatic cancer, bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; or uterine cancer.17.The compound according to claim 16, wherein the compound is administered separately, sequentially or simultaneously with additional DNA damage response (DDR) targeting anti-cancer agent(s), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).18.A method of treating or preventing diseases or disorders mediated by USP1 in a subject, comprising administering to the subject at least one compound according to any one of claims 1 to 13, or a tautomer, stereoisomer, prodrug, crystal form, isotopically labeled form, pharmaceutically acceptable salt, hydrate, or solvate thereof.19.The method of claim 18, wherein the diseases or disorders mediated by USP1 are cancer, preferably lung cancer, non-small cell lung cancer (NSCLC), ovarian cancer, breast cancer, bladder cancer, CNS cancer, lymphoma, esophageal cancer, head and neck cancer, colorectal cancer, myeloma, sarcoma, gastric cancer, liver cancer, cervical cancer, brain cancer including glioma, glioblastoma, astrocytoma, medulloblastoma, and meningioma; skin cancer including melanoma, kidney cancer, colon cancer, osteosarcoma, pancreatic cancer, bone cancer, including chondrosarcoma; soft tissue cancer, including rhabdoid; or uterine cancer.20.The method of any one of claims 18 to 19, further comprising administering to the subject additional DDR targeting anti-cancer agent(s), preferably PARP inhibitors (e.g., niraparib, olaparib, rucaparib, talazoparib, veliparib, E7016), ATR inhibitors (e.g., VE-821, VE-822, VX-970 (also known as M6620 or berzosertib), AZD6738 (e.g., ceralasertib), BAY 1895344, M4344), ATM inhibitors (e.g., AZD0156, AZD0156, AZD1390, M3541), DNA-PK Inhibitors (e.g., CC-115, M3814 (nedisertib or peposertib), AZD7648), CHK1 / 2 Inhibitors (e.g., UCN-01, AZD7762, LY2603618, MK-8776, GDC-0575, LY2606368 (e.g., prexasertib)), WEE1 Inhibitors (e.g., Adavosertib (MK-1775, or AZD1775), PLK1 Inhibitors (e.g., Volasertib (BI 6727), Onvansertib (e.g., PCM-075, NMS-1286937), APE1 inhibitors (e.g., methoxyamine), or Topoisomerase inhibitors (e.g., belotecan, CRLX101, irinotecan, LMP 400, LMP 776, NKTR-102, doxorubicin, epirubicin, etoposide, idarubicin, mitoxantrone, teniposide).

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